KRAS modulators and uses thereof

Abstract

Provided herein are compounds, such as compounds of Formula (I), Formula (l-A), Formula (l-AA), or Formula (l-BB), or pharmaceutically acceptable salts of any one thereof, useful for modulating KRAS GD12 and / or other G12 mutants. (I)

Description

Attorney Docket No. 55172-736601 KRAS MODULATORS AND USES THEREOF

[0001] This application claims the benefit of U.S. Provisional Patent Applications No. 63 / 579,356 filed on August 29, 2023, the entire contents of which is incorporated herein by reference. BACKGROUND OF THE INVENTION

[0002] The small GTPase protein Kirsten Rat Sarcoma 2 Viral Oncogene Homolog (KRAS) is a member of the Ras family of cell signaling switches, regulating growth and survival of normal and cancerous cells (e.g., see Cully, M. and J. Downward, SnapShot: Ras Signaling. Cell, 2008. 133(7): p.1292-1292 e1). KRAS mutations drive approximately 25% of human cancers by aberrant regulation of the mitogen-activated protein kinase (MAPK) signaling cascade and other effector pathways (e.g., see Stephen, A.G., et al., Dragging ras back in the ring. Cancer Cell, 2014.25(3): p.272-81). Though Ras has been recognized as a target in cancer for about 40 years, Ras-driven cancers remain among the most difficult to treat due to insensitivity to available targeted therapies. Ras, encoded by the three major genes KRAS, NRAS and HRAS, has the highest frequency of mutation of any oncogene. All oncogenic Ras mutations drive the switch to accumulate in the active GTP-bound state. The most common Ras mutation found across human tumor types is KRAS G12D (e.g., see The AACR Project GENIE Consortium. Cancer Discovery, 2017.7(8): p.818-831. Dataset Version 4). Activating mutations in codon 12 impair the small GTPases’ ability to perform their role in hydrolyzing GTP. This regulatory impairment is fundamental for initiating and maintaining tumor progression.

[0003] Despite extensive efforts, small molecules have not been identified which block effector binding or restore GTPase activating protein (GAP) sensitivity, though some have been found which block interaction of Ras with the guanine nucleotide exchange factor (GEF), SOS, which activates Ras at the plasma membrane. KRAS G12C mutations, most common in lung adenocarcinoma, have been clinically shown to be susceptible to direct inhibition by covalent modification with small molecule inhibitors trapping the protein in the inactive GDP-bound state. KRAS G12D mutation confers a significantly slower intrinsic rate of GTP hydrolysis than G12C, resulting in more constitutive activation. Thus, pharmacological targeting the of inactive state is unlikely to achieve similar results against G12D, despite the existence of a similar binding pocket in the GDP-state. Additionally, a cysteine present at the site of the activating mutation yields itself to covalent chemistry, while aspartic acid does not provide typical medicinal chemistry approaches for selective covalent modification.Attorney Docket No. 55172-736601

[0004] In order to potentially exploit the accumulation of KRAS G12D and other mutant variants in the GTP-bound state as a vulnerability to achieve selective inhibition of cancer cells while sparing normal Ras function, it is attractive for small molecule inhibitors to bind selectively to the GTP-state and stabilize a conformation that is incompetent for oncogenic signaling interactions with effector proteins. Furthermore, it has been shown that only constitutive activation of Raf, MEK and ERK kinases in the MAPK cascade downstream of Ras can bypass the requirement for Ras proteins in proliferative signaling (e.g., see Drosten, M., et al., Genetic analysis of Ras signaling pathways in cell proliferation, migration and survival. EMBO J, 2010.29(6): p.1091-104). As all evidence has indicated that MAPK signaling is essential for the growth effects of Ras in cancer, KRAS-mutant-selective inhibition in this pathway is considered the critical functional readout for potential clinical benefit of novel therapeutic approaches. Thus, there is a need to develop new inhibitors for KRAS-driven cancers that demonstrate inhibition of MAPK signals via a mechanism of action that is selective for binding to the active GTP-bound state over the inactive GDP-bound state. INCORPORATION BY REFERENCE

[0005] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material. SUMMARY OF THE INVENTION

[0006] In certain aspects, the present disclosure provides a compound represented by the structure of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof wherein: Xwherein t represents the point of connection between X and YA is selected from a 5- to 15-membered heterocycle and C5-C12carbocycle, wherein the 5- to 15- membered heterocycle and C5-C12 carbocycle are each optionally substituted with one or more substituents independently selected from R50; each R50is selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, - NHCN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, - NHCN, C1-6 alkyl-N(R20)2, C1-6 alkyl-SO2R20, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 5- to 12- membered heterocycle and C3-C12 carbocycle, wherein the 5- to 12-membered heterocycle and C3-C12 carbocycle are each optionally substituted independently with one or more R2*; each R2*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, - NHCN, C1-6alkyl-N(R20)2, C1-6alkyl-SO2R20, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 5- to 12- membered heterocycle and C3-C12 carbocycle; B is selected from a 7- to 15-membered fused heterocycle and C7-C15fused carbocycle, wherein the 7- to 15-membered fused heterocycle and C7-C15 fused carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =O, -N(R21)2, -B(OR21)2, -OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, - C(O)N(R21)2, -C(O)NR21OR21, -N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, - C(O)R21, C(O)OR21, -OC(O)R21, -OC(O)N(R21)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle; -3-R2is selected from hydrogen, heterocycle, Cl-C6alkyl, -L-heterocycle, -L-N(R20)2, -L-OR20, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R20)2, -L-Cl-C6 haloalkyl, -L-OR20, -L-NR20C(O)-aryl, -L-COOH, -L-NR20S(O)2(R20), -L-S(O)2N(R20)2, -L- N(R20)C(O)(OR20), -L-OC(O)N(R20)2, and -L-C(=O)OCl-C6alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of -L- NR20C(O)-aryl, the aryl portion of -L-NR20C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6 alkyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6cyanoalkyl, C1-6hydroxyalkyl, and C1-6haloalkyl; n is selected from 0, 1, 2, 3, and 4; m is selected from 1 and 2; Y is selected from a bond, -O-, -S-, and -N(R5)-; each R5is independently selected from hydrogen and C1-C6 alkyl; each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, oxo, Cl-C3haloalkyl, C1-C3alkoxy, Cl-C3alkyl-N3, cyano, =CH2, =CHF, =CF2, =NO-Cl-C3alkyl, Cl-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)-C1-C3 alkyl-N(R5)2, -CH2OC(O)NCF3(R5), -CH2O-Cl-C6alkyl, -C(O)N(R5)2, tert- butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3alkoxy)Cl-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Cl-C3 alkoxy, -CH2OC(O)N(R5)2, - CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl(C1- C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl, -OC(O)heterocycle, -O- Cl-C3alkyl, -O-Cl-C6haloalkyl, -C1-C3alkyl-O-Cl-C6haloalkyl, C1-6alkyl-N(R20)2, -SF5, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -(CH2)0-1S- heterocycle , -(CH2)0-1-O-heterocycle, -(CH2)0-1-O-phenyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(Cl-C3alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Cl-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; wherein the alkyl of -CH2O-Cl-C6 alkyl is optionally substituted with one or more substituents selected from halogen and C3-C6carbocycle; and wherein the heterocycle of CH heterocyclyl is optionally substituted with oxo; and whereinthe phenyl of -(CH2)0-1-O-phenyl is optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, SF5, C1-6 alkyl-OR20, -OR20; wherein the heterocycle of -(CH2)0-1-O-heterocycle and -(CH2)0-1-S-heterocycle are each optionally substituted with one or more substituents selected from C1-6alkyl, C1-6haloalkyl, C1-6alkyl-OR20, and -OR20; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, Cl-C4 alkyl, Cl-C4 alkoxy, Cl- C4haloalkyl, Cl-C4hydroxyalkyl, and -N(R5)2; each L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from hydroxy, Cl-C4 hydroxyalkyl, Cl-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle.

[0007] In some embodiments, a compound or salt of Formula (I) is represented byF l (I A) or a p

[0008] In some embodiments, a compound or salt of Formula (I) or Formula (I-A), B is represented , wherein C is selected from a C5-C8 carbocycle and 5- to 8- membered he the C5-C8 carbocycle and 5- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, - OMe, -N(R20)2, -C(O)R20, =O, -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0009] In some embodiments, a compound or salt of Formula (I) is represented by Formula (I-AA), or a pharmaceutically accewherein C is selected from a C5-C8 carbocycle and 5- to 8-membered heterocycle, wherein the C5-C8 carbocycle and 5- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -OMe, -N(R20)2, -C(O)R20, =O, - CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0010] In some embodiments, a compound or salt of Formula (I) is represented byFormula (I-BB), or a pharmaceutically acceptable salt; wherein C is selected from a C5-C8carbocycle and 5- to 8-membered heterocycle, wherein the C5-C8 carbocycle and 5- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -OMe, -N(R20)2, -C(O)R20, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0011] In certain embodiments, the disclosure provides a pharmaceutical composition comprising a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I- BB), and a pharmaceutically acceptable excipient.

[0012] In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB).In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB) and a pharmaceutically acceptable excipient. In certain embodiments, the disclosure provides a method of treating a disease or disorder, using a pharmaceutical composition compromising a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB).

[0013] In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and / or other G12 mutants, using a compound or salt of Formula (I), Formula (I-A), Formula (I- AA), or Formula (I-BB). In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and / or other G12 mutants, using a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB) and a pharmaceutically acceptable excipient. In certain embodiments, the disclosure provides a method of inhibiting KRas G12D and / or other G12 mutants, using a pharmaceutical composition compromising a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB) and a pharmaceutically acceptable excipient. DETAILED DESCRIPTION OF THE INVENTION

[0014] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby. Definitions

[0015] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

[0016] As used in the specification and claims, the singular form “a”, “an” and “the” includes plural references unless the context clearly dictates otherwise.

[0017] The term “Cx-y” or “Cx-Cy” when used in conjunction with a chemical moiety, such as alkyl, alkenyl, or alkynyl is meant to include groups that contain from x to y carbons in the chain. For example, the term “C1-6alkyl” refers to saturated hydrocarbon groups, including straight- chain alkyl and branched-chain alkyl groups that contain from 1 to 6 carbons. For example –C1-6 alkyl- may be selected from methyl, ethyl, propyl, butyl, pentyl, and hexyl, any one of which is optionally substituted. The term –Cx-yalkylene- refers to a substituted or unsubstituted alkylene chain with from x to y carbons in the alkylene chain. For example –C1-6 alkylene- may be selected from methylene, ethylene, propylene, butylene, pentylene, and hexylene, any one of which is optionally substituted.

[0018] "Alkyl" as used herein refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, and preferably having from one to fifteen carbon atoms (i.e., C1-C15alkyl). In certain embodiments, an alkyl comprises one to thirteen carbon atoms (i.e., C1-C13 alkyl). In certain embodiments, an alkyl comprises one to eight carbon atoms (i.e., C1-C8 alkyl). In other embodiments, an alkyl comprises one to five carbon atoms (i.e., C1-C5alkyl). In other embodiments, an alkyl comprises one to four carbon atoms (i.e., C1-C4 alkyl). In other embodiments, an alkyl comprises one to three carbon atoms (i.e., C1-C3 alkyl). In other embodiments, an alkyl comprises one to two carbon atoms (i.e., C1-C2alkyl). In other embodiments, an alkyl comprises one carbon atom (i.e., C1alkyl). In other embodiments, an alkyl comprises five to fifteen carbon atoms (i.e., C5-C15alkyl). In other embodiments, an alkyl comprises five to eight carbon atoms (i.e., C5-C8 alkyl). In other embodiments, an alkyl comprises two to five carbon atoms (i.e., C2-C5 alkyl). In other embodiments, an alkyl comprises three to five carbon atoms (i.e., C3-C5alkyl). In certain embodiments, the alkyl group is selected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl (iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), 1-pentyl (n-pentyl). The alkyl is attached to the rest of the molecule by a single bond.

[0019] "Alkenyl" as used herein refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12alkenyl). In certain embodiments, an alkenyl comprises two to eight carbon atoms (i.e., C2-C8 alkenyl). In certain embodiments, an alkenyl comprises two to six carbon atoms (i.e., C2-C6 alkenyl). In other embodiments an alkenyl comprises two to four carbon atoms (ie C2-C4alkenyl) The alkenyl isattached to the rest of the molecule by a single bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e., allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

[0020] "Alkynyl" as used herein refers to a straight or branched hydrocarbon chain radical group consisting solely of carbon and hydrogen atoms, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms (i.e., C2-C12 alkynyl). In certain embodiments, an alkynyl comprises two to eight carbon atoms (i.e., C2-C8 alkynyl). In other embodiments, an alkynyl comprises two to six carbon atoms (i.e., C2-C6alkynyl). In other embodiments, an alkynyl comprises two to four carbon atoms (i.e., C2-C4 alkynyl). The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0021] The terms “Cx-yalkenyl” and “Cx-yalkynyl” as used herein refer to substituted or unsubstituted unsaturated aliphatic groups analogous in length and possible substitution to the alkyls described above, but that contain at least one double or triple bond, respectively. The term –Cx-yalkenylene- refers to a substituted or unsubstituted alkenylene chain with from x to y carbons in the alkenylene chain. For example, –C2-6alkenylene- may be selected from ethenylene, propenylene, butenylene, pentenylene, and hexenylene, any one of which is optionally substituted. An alkenylene chain may have one double bond or more than one double bond in the alkenylene chain. The term –Cx-yalkynylene- refers to a substituted or unsubstituted alkynylene chain with from x to y carbons in the alkenylene chain. For example, –C2-6alkenylene- may be selected from ethynylene, propynylene, butynylene, pentynylene, and hexynylene, any one of which is optionally substituted. An alkynylene chain may have one triple bond or more than one triple bond in the alkynylene chain.

[0022] “Alkylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing no unsaturation, and preferably having from one to twelve carbon atoms, for example, methylene, ethylene, propylene, butylene, and the like. The alkylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. In other embodiments, an alkylene comprises one to five carbon atoms (i.e., C1-C5alkylene). In other embodiments, an alkylene comprises one to four carbon atoms (i.e., C1-C4alkylene). In other embodiments, an alkylene comprises one to three carbon atoms (i.e., C1-C3 alkylene). In other embodiments, an alkylene comprises one to two carbon atoms (i.e., C1-C2 alkylene). In other embodiments, an alkylene comprises one carbon atom (ie C1alkylene) In other embodiments an alkylene comprises five to eight carbon atoms(i.e., C5-C8alkylene). In other embodiments, an alkylene comprises two to five carbon atoms (i.e., C2-C5 alkylene). In other embodiments, an alkylene comprises three to five carbon atoms (i.e., C3-C5 alkylene). Unless stated otherwise specifically in the specification, an alkylene chain is optionally substituted by one or more substituents such as those substituents described herein.

[0023] "Alkenylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon double bond, and preferably having from two to twelve carbon atoms. The alkenylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkenylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. In other embodiments, an alkenylene comprises two to five carbon atoms (i.e., C2-C5alkenylene). In other embodiments, an alkenylene comprises two to four carbon atoms (i.e., C2-C4 alkenylene). In other embodiments, an alkenylene comprises two to three carbon atoms (i.e., C2-C3 alkenylene). In other embodiments, an alkenylene comprises two carbon atom (i.e., C2alkenylene). In other embodiments, an alkenylene comprises five to eight carbon atoms (i.e., C5-C8 alkenylene). In other embodiments, an alkenylene comprises three to five carbon atoms (i.e., C3-C5 alkenylene). Unless stated otherwise specifically in the specification, an alkenylene chain is optionally substituted by one or more substituents such as those substituents described herein.

[0024] "Alkynylene" refers to a straight divalent hydrocarbon chain linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen, containing at least one carbon-carbon triple bond, and preferably having from two to twelve carbon atoms. The alkynylene chain is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the alkynylene chain to the rest of the molecule and to the radical group are through the terminal carbons respectively. In other embodiments, an alkynylene comprises two to five carbon atoms (i.e., C2-C5 alkynylene). In other embodiments, an alkynylene comprises two to four carbon atoms (i.e., C2-C4 alkynylene). In other embodiments, an alkynylene comprises two to three carbon atoms (i.e., C2-C3alkynylene). In other embodiments, an alkynylene comprises two carbon atom (i.e., C2 alkynylene). In other embodiments, an alkynylene comprises five to eight carbon atoms (i.e., C5- C8alkynylene). In other embodiments, an alkynylene comprises three to five carbon atoms (i.e., C3-C5alkynylene). Unless stated otherwise specifically in the specification, an alkynylene chain is optionally substituted by one or more substituents such as those substituents described herein.

[0025] "Halo" or "halogen" as used herein refers to halogen substituents such as bromo, chloro fluoro and iodo substituents

[0026] "Haloalkyl" as used herein refers to an alkyl radical, as defined above, that is substituted by one or more halogen radicals, for example, trifluoromethyl, dichloromethyl, bromomethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Examples of halogen substituted alkanes (“haloalkanes”) include halomethane (e.g., chloromethane, bromomethane, fluoromethane, iodomethane), di-and trihalomethane (e.g., trichloromethane, tribromomethane, trifluoromethane, triiodomethane), 1-haloethane, 2-haloethane, 1,2- dihaloethane, and any other suitable combinations of alkanes (or substituted alkanes) and halogens. When an alkyl group is substituted with more than one halogen radicals, each halogen may be independently selected, for example 1-chloro,2-bromoethane.

[0027] "Alkoxy" refers to a radical bonded through an oxygen atom of the formula –O-alkyl, where alkyl is an alkyl chain as defined above.

[0028] "Fluoroalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, trifluoromethyl, difluoromethyl, fluoromethyl, 2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like.

[0029] "Aminoalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more amine radicals, for example, propan-2-amine, butane-1,2-diamine, pentane-1,2,4-triamine and the like.

[0030] "Hydroxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more hydroxy radicals, for example, propan-1-ol, butane-1,4-diol, pentane-1,2,4-triol, and the like.

[0031] "Alkoxyalkyl" refers to an alkyl radical, as defined above, that is substituted by one or more alkoxy radicals, for example, methoxymethane, 1,3-dimethoxybutane, 1-methoxypropane, 2-ethoxypentane, and the like.

[0032] "Cyanoalkyl" as used herein refers to an alkyl radical, as defined above, that is substituted by one or more cyano radicals, for example, acetonitrile, 2-ethyl-3- methylsuccinonitrile, butyronitrile, and the like.

[0033] The term “carbocycle” as used herein refers to a saturated, unsaturated or aromatic ring in which each atom of the ring is carbon atom. Carbocycle includes 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. Each ring of a bicyclic carbocycle may be selected from saturated, unsaturated, and aromatic rings. In an exemplary embodiment, an aromatic ring, e.g., phenyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, or cyclohexene. A bicyclic carbocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. Abicyclic carbocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5-6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Exemplary carbocycles include cyclopentyl, cyclohexyl, cyclohexenyl, adamantyl, phenyl, indanyl, and naphthyl. Bicyclic carbocycles may be fused, bridged, or spiro-ring systems. In some cases, spiro-ring carbocycles have at least two molecular rings with only one common atom.

[0034] "Aryl" as used herein refers to a radical derived from an aromatic monocyclic or aromatic multicyclic hydrocarbon ring system by removing a hydrogen atom from a ring carbon atom. The aromatic monocyclic or aromatic multicyclic hydrocarbon ring system contains only hydrogen and carbon and from five to eighteen carbon atoms, where at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The ring system from which aryl groups are derived include, but are not limited to, groups such as benzene, fluorene, indane, indene, tetralin and naphthalene.

[0035] The term “unsaturated carbocycle” refers to carbocycles with at least one degree of unsaturation and excluding aromatic carbocycles. Examples of unsaturated carbocycles include cyclohexadiene, cyclohexene, and cyclopentene.

[0036] "Cycloalkyl" refers to a fully saturated monocyclic or polycyclic hydrocarbon radical consisting solely of carbon and hydrogen atoms, which includes fused or bridged ring systems, and preferably having from three to twelve carbon atoms. In certain embodiments, a cycloalkyl comprises three to ten carbon atoms. In other embodiments, a cycloalkyl comprises five to seven carbon atoms. The cycloalkyl may be attached to the rest of the molecule by a single bond. Examples of monocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic cycloalkyl radicals include, for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl), norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like.

[0037] The term “Cx-y carbocycle” or “Cx-Cy carbocycle” is meant to include groups that contain from x to y carbons in the cycle. For example, the term “C3-6 carbocycle” refers to a saturated, unsaturated, or aromatic ring comprising from 3 to 6 carbons. For example –C3-6carbocycle- may be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and phenyl, any one of which is optionally substituted.

[0038] The term “carbocyclene” refers to a divalent ring, linking the rest of the molecule to a radical group, consisting solely of carbon and hydrogen atoms. The carbocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The pointsare through any two carbons respectively. Carbocyclene includes arylene and cycloalkylene. The term therefore distinguishes carbocyclene from heterocyclene in which the divalent ring comprises at least one atom that is different from a carbon atom. The heterocyclene is attached to the rest of the molecule through a single bond and to the radical group through a single bond. The points of attachment of the heterocyclene are to the rest of the molecule and to the radical group through any two atoms respectively, valency permitting. Heterocyclene includes heteroarylene and heterocycloalkylene. Carbocyclene and heterocyclene may each be optionally substituted by one or more substituents such as those substituents described herein.

[0039] The term “heterocycle” as used herein refers to a saturated, unsaturated or aromatic ring comprising one or more heteroatoms. Exemplary heteroatoms include N, O, Si, P, B, and S atoms. The heterocycle may be attached to the rest of the molecule through any atom of the heterocycle, valence permitting, such as a carbon or nitrogen atom of the heterocycle. Heterocycles include 3- to 10-membered monocyclic rings, 6- to 12-membered bicyclic rings, and 6- to 12-membered bridged rings. A bicyclic heterocycle includes any combination of saturated, unsaturated and aromatic bicyclic rings, as valence permits. In an exemplary embodiment, an aromatic ring, e.g., pyridyl, may be fused to a saturated or unsaturated ring, e.g., cyclohexane, cyclopentane, morpholine, piperidine or cyclohexene. A bicyclic heterocycle includes any combination of ring sizes such as 4-5 fused ring systems, 5-5 fused ring systems, 5- 6 fused ring systems, 6-6 fused ring systems, 5-7 fused ring systems, 6-7 fused ring systems, 5-8 fused ring systems, and 6-8 fused ring systems. Bicyclic heterocycles may be fused, bridged, or spiro-ring systems. A spiro-ring system may be referred as a “spiroheterocycle”, “spiro heterocycle”, or “spiro-heterocycle”. In some cases, spiro-heterocycles, spiro heterocycles, or spiroheterocycles have at least two molecular rings with only one common atom. The spiro- heterocycle, spiro heterocycle, or spiroheterocycle comprises one or more heteroatoms.

[0040] “Heteroaryl" or “aromatic heterocycle” refers to a radical derived from a heteroaromatic ring radical that comprises one to eleven carbon atoms and at least one heteroatom wherein each heteroatom may be selected from N, O, and S. As used herein, the heteroaryl ring may be selected from monocyclic or bicyclic and fused or bridged ring systems rings wherein at least one of the rings in the ring system is aromatic, i.e., it contains a cyclic, delocalized (4n+2) ^–electron system in accordance with the Hückel theory. The heteroatom(s) in the heteroaryl radical may be optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the heteroaryl, valence permitting, such as a carbon or nitrogen atom of the heteroaryl. Examples of heteroaryls include, but are not limited to, pyridine, pyrimidine, oxazole, furan, thioph

[0041] An “X-membered heteroaryl” refers to the number of endocylic atoms, i.e., X, in the ring. For example, a 5-membered heteroaryl ring or 5-membered aromatic heterocycle has 5 endocyclic atoms, e.g., triazole, oxazole, thiophene, etc.

[0042] The term “unsaturated heterocycle” refers to heterocycles with at least one degree of unsaturation and excluding aromatic heterocycles. Examples of unsaturated heterocycles include dihydropyrrole, dihydrofuran, oxazoline, pyrazoline, and dihydropyridine. Heterocycles may be optionally substituted by one or more substituents such as those substituents described herein.

[0043] “Substituted” refers to moieties having substituents replacing a hydrogen on one or more carbons or substitutable heteroatoms, e.g., an NH or NH2 of a compound. It will be understood that “substitution” or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, i.e., a compound which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. In certain embodiments, substituted refers to moieties having substituents replacing two hydrogen atoms on the same carbon atom, such as substituting the two hydrogen atoms on a single carbon with an oxo, imino or thioxo group. As used herein, the term “substituted” is contemplated to include all permissible substituents of organic compounds. In a broad aspect, the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds. The permissible substituents can be one or more and the same or different for appropriate organic compounds.

[0044] As used herein, the term “optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl group may or may not be substituted and that the description includes both substituted aryl groups and aryl groups having no substitution.

[0045] As used herein, the term “electrophile” or “electrophilic moiety” is any moiety capable of reacting with a nucleophile (e.g., a moiety having a lone pair of electrons, a negative charge, a partial negative charge and / or an excess of electrons, for example an —SH group). Electrophiles typically are electron poor or comprise atoms which are electron poor. In certain embodiments, an electrophile contains a positive charge or partial positive charge, has a resonance structure which contains a positive charge or partial positive charge, or is a moiety in which delocalization or polarization of electrons results in one or more atoms which contains a positive charge orpartial positive charge. In some embodiments, an electrophile comprises a conjugated double bond, for example an α,β-unsaturated carbonyl or α,β-unsaturated thiocarbonyl compound.

[0046] In some embodiments, substituents may include any substituents described herein, for example: halogen, hydroxy, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazino (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N (Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2), and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, and heteroarylalkyl any of which may be optionally substituted by alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N (Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2(where t is 1 or 2); wherein each Rais independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl, or heteroarylalkyl, wherein each Ra, valence permitting, may be optionally substituted with alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, oxo (=O), thioxo (=S), cyano (-CN), nitro (-NO2), imino (=N-H), oximo (=N-OH), hydrazine (=N- NH2), -Rb-ORa, -Rb-OC(O)-Ra, -Rb-OC(O)-ORa, -Rb-OC(O)-N(Ra)2, -Rb-N(Ra)2, -Rb-C(O)Ra, -Rb-C(O)ORa, -Rb-C(O)N(Ra)2, -Rb-O-Rc-C(O)N(Ra)2, -Rb-N(Ra)C(O)ORa, -Rb-N(Ra)C(O)Ra, -Rb-N (Ra)S(O)tRa(where t is 1 or 2), -Rb-S(O)tRa(where t is 1 or 2), -Rb-S(O)tORa(where t is 1 or 2) and -Rb-S(O)tN(Ra)2 (where t is 1 or 2); and wherein each Rbis independently selected from a direct bond or a straight or branched alkylene, alkenylene, or alkynylene chain, and each Rcis a straight or branched alkylene, alkenylene or alkynylene chain. It will be understood by those skilled in the art that substituents can themselves be substituted, if appropriate.

[0047] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0048] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen- free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0049] The terms "subject," "individual," and "patient" may be used interchangeably and refer to humans, the as well as non-human mammals (e.g., non-human primates, canines, equines, felines, porcines, bovines, ungulates, lagomorphs, and the like). In various embodiments, the subject can be a human (e.g., adult male, adult female, adolescent male, adolescent female, male child, female child) under the care of a physician or other health worker in a hospital, as an outpatient, or other clinical context. In certain embodiments, the subject may not be under the care or prescription of a physician or other health worker.

[0050] As used herein, the phrase "a subject in need thereof" refers to a subject, as described infra, that suffers from, or is at risk for, a pathology to be prophylactically or therapeutically treated with a compound or salt described herein.

[0051] The terms “administer”, “administered”, “administers” and “administering” are defined as providing a composition to a subject via a route known in the art, including but not limited to intravenous, intraarterial, oral, parenteral, buccal, topical, transdermal, rectal, intramuscular, subcutaneous, intraosseous, transmucosal, or intraperitoneal routes of administration. In certain embodiments, oral routes of administering a composition can be used. The terms ““administer”, “administered”, “administers” and “administering” a compound should be understood to mean providing a compound of the invention or a prodrug of a compound of the invention to the individual in need

[0052] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g., reduction of proliferation or down regulation of activity of a target protein. The specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0053] As used herein, “treatment” or “treating” refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. In certain embodiments, treatment or treating involves administering a compound or composition disclosed herein to a subject. A therapeutic benefit may include the eradication or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0054] In certain embodiments, the term “prevent” or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0055] A “therapeutic effect,” as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit as described above. A prophylactic effect includes delaying or eliminating the appearance of a disease or condition, delaying or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof.

[0056] The term “inhibit”, “selective inhibition” or “selectively inhibit” as referred to a biologically active agent refers to the agent’s ability to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target.

[0057] The term “targeted agent” or “targeted therapy” as described herein referred to a therapy that uses specific drugs to target specific genes, protein, or active sites involved in the development, survival, and proliferation of cancer cells.

[0058] It is intended that every maximum numerical limitation given throughout this specification includes every lower numerical limitation, as if such lower numerical limitations were expressly written herein. Every minimum numerical limitation given throughout this specification will include every higher numerical limitation, as if such higher numerical limitations were expressly written herein. Every numerical range given throughout this specification will include every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein.

[0059] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. Compounds

[0060] In certain aspects, the present disclosure provides a compound represented by the structure of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof wherein: Xwherein t represents the point of connection between X and YA is selected from a 5- to 15-membered heterocycle and C5-C12carbocycle, wherein the 5- to 15- membered heterocycle and C5-C12 carbocycle are each optionally substituted with one or more substituents independently selected from R50; each R50is selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, - NHCN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, - NHCN, C1-6 alkyl-N(R20)2, C1-6 alkyl-SO2R20, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 5- to 12- membered heterocycle and C3-C12 carbocycle, wherein the 5- to 12-membered heterocycle and C3-C12 carbocycle are each optionally substituted independently with one or more R2*; each R2*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, - NHCN, C1-6alkyl-N(R20)2, C1-6alkyl-SO2R20, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, 5- to 12- membered heterocycle and C3-C12 carbocycle; B is selected from a 7- to 15-membered fused heterocycle and C7-C15fused carbocycle, wherein the 7- to 15-membered fused heterocycle and C7-C15 fused carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =O, -N(R21)2, -B(OR21)2, -OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, - C(O)N(R21)2, -C(O)NR21OR21, -N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, - C(O)R21, C(O)OR21, -OC(O)R21, -OC(O)N(R21)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle;R2is selected from hydrogen, heterocycle, Cl-C6alkyl, -L-heterocycle, -L-N(R20)2, -L-OR20, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R20)2, -L-Cl-C6 haloalkyl, -L-OR20, -L-NR20C(O)-aryl, -L-COOH, -L-NR20S(O)2(R20), -L-S(O)2N(R20)2, - L-N(R20)C(O)(OR20), -L-OC(O)N(R20)2, and -L-C(=O)OCl-C6alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the - L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of -L-NR20C(O)-aryl, the aryl portion of -L-NR20C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6 alkyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6cyanoalkyl, C1-6hydroxyalkyl, and C1-6haloalkyl; n is selected from 0, 1, 2, 3, and 4; m is selected from 1 and 2; Y is selected from a bond, -O-, -S-, and -N(R5)-; each R5is independently selected from hydrogen and C1-C6 alkyl; each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, oxo, Cl-C3haloalkyl, C1-C3alkoxy, Cl-C3alkyl-N3, cyano, =CH2, =CHF, =CF2, =NO-Cl-C3alkyl, Cl-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)-C1-C3 alkyl-N(R5)2, -CH2OC(O)NCF3(R5), -CH2O-Cl-C6alkyl, -C(O)N(R5)2, tert- butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3alkoxy)Cl-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Cl-C3 alkoxy, -CH2OC(O)N(R5)2, - CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl(C1- C3 alkyl)N(CH3)2, -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl, -OC(O)heterocycle, -O- Cl-C3alkyl, -O-Cl-C6haloalkyl, -C1-C3alkyl-O-Cl-C6haloalkyl, C1-6alkyl-N(R20)2, -SF5, - S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -(CH2)0-1S- heterocycle , -(CH2)0-1-O-heterocycle, -(CH2)0-1-O-phenyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3alkyl)(Cl-C3alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Cl-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; wherein the alkyl of -CH2O-Cl-C6 alkyl is optionally substituted with one or more substituents selected from halogen and C3-C6carbocycle; and wherein the heterocycle of CH heterocycle is optionally substituted with oxo; and whereinthe phenyl of -(CH2)0-1-O-phenyl is optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, SF5, C1-6 alkyl-OR20, -OR20; wherein the heterocycle of -(CH2)0-1-O-heterocycle and -(CH2)0-1-S-heterocycle are each optionally substituted with one or more substituents selected from C1-6alkyl, C1-6haloalkyl, C1-6alkyl- OR20, and -OR20; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, Cl-C4alkyl, Cl-C4alkoxy, Cl- C4 haloalkyl, Cl-C4 hydroxyalkyl, and -N(R5)2; each L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from hydroxy, Cl-C4hydroxyalkyl, Cl-C4alkyl, C3-C6carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, - NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle; and each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, - NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle.

[0061] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is bicyclic. In some cases, X is tricyclic. In some cases, X is tetracyclic. In some cases, X has heteroatoms selected from nitrogen, and oxygen. In some cases, X has heteroatoms selected from nitrogen, and sulfur. In some cases, X has heteroatoms selected from nitrogen. In some cases, X has 1 sulfur atom. In some cases, X has 1 oxygen atom. In some cases, X has 3 nitrogen atoms. In someone sulfur atom. In some cases, X has 4 nitrogen atoms. In some cases, X is selected from , , , ach oR50. In some cases, X is selected from and, each of which is optionally substituted with one or more substituentsi , , , ach oR50. I , ,h is optionally substituted with one or more substituents independently selected from R50. In somecases, X is selected from , each of which is optionally rom R50. In some cases, each Rs connected to t e port on o . n some cases, s a brdged heterocycle.

[0062] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from halogen, -OR20, -S(O)2(R20), -C(O)N(R20)2, -N(R20)2, -C(O)R20, -C(O)OR20, =O, -CN, -NHCN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*. In some cases, each R50is independently selected from halogen, -OR20, -C(O)N(R20)2, -N(R20)2, -C(O)R20, =O, -CN, -NHCN, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*. In some cases, each R50is independently selected from halogen, -C(O)N(R20)2, -N(R20)2, -C(O)R20, =O, -CN, -NHCN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and 5- to 12-membered heterocycle, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*.

[0063] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from -CN, =O, -OH, C1-6 alkyl, - C(O)R20, -C(O)N(R20)2, C3-C6 carbocycle, 5- to 6-membered heterocycle, wherein the C1-6 alkyl, C3-C6carbocycle, and 5- to 6-membered heterocycle are each optionally substituted independently with one or more R1*, wherein each R1*is independently selected from halogen, -OR20, -N(R20)2, =O, -CN, -NHCN, 5- to 12-membered heterocycle and C3-C6 carbocycle, wherein the 5- to 6- membered heterocycle and C3-C12 carbocycle are each optionally substituted independently with one or more R2*, and wherein each R2*is independently selected from halogen, -OR20, -N(R20)2, - C(O)OR20, and C1-6 hydroxyalkyl.

[0064] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from -CN, =O, C1-6alkyl, -C(O)R20, -C(O)N(R20)2, C3-C6 carbocycle, 5- to 6-membered heterocycle, wherein the C1-6 alkyl, C3-C6 carbocycle, and 5- to 6-membered heterocycle are each optionally substituted independently with one oCN, -NHCN, 5- to 12-membered heterocycle and C3-C6carbocycle, wherein the 5- to 6-membered heterocycle and C3-C12 carbocycle are each optionally substituted independently with one or more R2*, and wherein each R2*is independently selected from halogen, -OR20, -N(R20)2, -C(O)OR20, and C1-6hydroxyalkyl.

[0065] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from -CN, =O, C1-6 alkyl, -C(O)R20, -C(O)N(R20)2, C3-C5carbocycle, 5- to 6-membered heterocycle, wherein the C1-6alkyl, C3-C5carbocycle and 5- to 6-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -OR20, -N(R20)2, =O, -CN, - NHCN, 5- to 6-membered heterocycle and C3-C6carbocycle, wherein the 5- to 6-membered heterocycle and C3-C6carbocycle are each optionally substituted independently with one or more R2*; each R2*is independently selected from halogen, -OR20, -N(R20)2, -C(O)OR20, and C1-6 hydroxyalkyl.

[0066] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from -CN, =O, -OH, and C1-6 alkyl.

[0067] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from =O, and C1-6alkyl.

[0068] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from =O.

[0069] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R1*is independently selected from halogen, -OR20, -N(R20)2, =O, -CN, -NHCN, 5- to 6-membered heterocycle and C3-C6 carbocycle, wherein the 5- to 6-membered heterocycle and C3-C6 carbocycle are each optionally substituted independently with one or more R2*. In some cases, each R1*is independently selected from 5- to 6-membered heterocycle and C3- C6 carbocycle, wherein the 5- to 6-membered heterocycle and C3-C6 carbocycle are each optionally substituted independently with one or more R2*. In some cases, the heterocycle is a heteroaryl. In some cases, the heterocycle is an unsaturated heterocycle. In some cases, the heterocycle is a saturated heterocycle.

[0070] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R2*is independently selected from halogen, -OR20, -N(R20)2, - C(O)OR20, and C1-6hydroxyalkyl. In some cases, each R2*is independently selected from -NH2. In some cases, each R2*is independently selected from -OR20, and -N(R20)2.

[0071] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from -CN, =O, C1-6 alkyl, -C(O)R20, -C(O)N(R20)2, 5- to 12-membered heterocycle, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C5carbocycle and 5- to 6-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -OR20, -N(R20)2, =O, -CN, -NHCN, 5- to 12-membered heterocycle and C3-C6 carbocycle, wherein the 5- to 6-membered heterocycle and C3-C12carbocycle are each optionally substituted independently with one or more R2*; and each R2*is independently selected from halogen, -OR20, -N(R20)2, -C(O)OR20, and C1-6 hydroxyalkyl.

[0072] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from -CN, =O, and C1-6alkyl, wherein the C1-6 alkyl is optionally substituted independently with one or more R1*. In some cases, each R1*is independently selected from halogen, -OH, -N(R20)2, =O, -CN, 5- to 6-membered heterocycle and C3-C6carbocycle, wherein the 5- to 6-membered heterocycle and C3-C6carbocycle are each optionally substituted independently with one or more R2*.

[0073] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from -CH3, =O, -C ,, , 50isindependently selected from ,rom [0, , , mula (I-AA), or Formula (I-BB), each R50is independently selected from -CN, and C1-6alkyl, wherein the C1-6 alkyl is optionally substituted independently with one or more R1*. In some cases, each R1*is independently selected from -OH, -CN, 5- to 6-membered heterocycle, wherein the 5- to 6- membered heterocycle is optionally substituted independently with one or more R2*. In some cases, e , and

[0075] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from -CN, and C1-6 alkyl, wherein the C1-6alkyl is substituted independently with one or more R1*. In some cases, each R50is independently selected from -CN, and C1alkyl, wherein the C1alkyl is substituted independently with one or more R1*In some cases each R1*is independently selected from 5 to 6 memberedheterocycle, wherein the 5- to 6-membered heterocycle is optionally substituted independently with one or more R2*. In some cases, the heterocycle has at least one nitrogen. In some cases, the heterocycle has only one nitrogen. In some cases, the heterocycle has at least one oxygen atom. In some cases, R1*is , which is optionally substituted independently with one or more R2*. Ins1*and omecases, the heterocycle of R1*is selected from , each of which is optionally substituted independently with ca2*ses, each R is independently selected from halogen, C1-6 alkyl, -C(O)OR20, and -N(R20)2. In some cases, each R2*is independently selected from -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)2, and C1-10alkyl. In some cases, each R2*is independently selected from halogen, -OH, -CN, -N(R21)2, -C(O)N(R21)2, C1-10alkyl, and -C1-10 haloalkyl. In some cases, at least one R2*is independently selected from halogen, C1-6 alkyl, -C(O)OR20, and -N(R20)2. In some cases, each R2*is independently selected from -CH3, - . In some cases, at least one R2*is independently selected from -Cl, -, . ases, at least one R2*is -NH2. In some cases, R1*is selected from ses, e ,

[0076] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from -CN, ,,

[0077] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (,

[0078] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected from -CN, and optionally substituted C1-6alkyl. In some cases, each R50is selected fro,R1*F F . In some cases, each R50is selected from -CNIn some cases, each R50is selected from -CN and . In some cases, R50is selectedfrom . In some cases, R50is selected from . In some cases, R1*is selected from 5- to 12- red hetero2*cycle, which is optionallstituted independently with one or more R . In some cases, R1*is selected from a 5- to 8-membered heterocycle, which is optionally substituted independently with one or more R2*. In some cases, R1*is selected from an optionally substituted 5- to 6-membered heterocycle, which is optionally substituted independently with one or more R2*. In some cases, R1*is selected from a 5- to 6-membered heteroaryl, which is optionally substituted independently with one or more R2*. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least two nitrogen atoms. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms. In some cases, the heterocycle has only 2 nitrogen atoms and no other heteroatoms. In some cases, R1*is selected from , each of which is optionally substituted indp y . s, R1*is selected from , which is optionally substituted independently with one or more R2*. Insome cases, R1*is selected from , each of whichis optionally substituted independently with one or more R2*. In some cases, R1*is selected fromeach of which is optionally substituted independently with one or more R2*. In some cases, each R2*is independently selected from halogen, -OH, -CN, -N(R20)2, - C(O)N(R20)2, C1-10alkyl, and -C1-10haloalkyl. In some cases, each R20is independently selected from hydrogen; and C1-6alkyl, wherein the C1-6alkyl is optionally substituted with one or more substiheterocycle. In some cases, each R2*is independently selected from is selected from halogen, C1-6 , ), - N(1-6a y)2, an1-10a y. n some cases, eac s nepenenty seecte rom -2, and C1-10alkyl. In some cases, each R2*is independently selected from -NH2. In some cases, R1*is s . I s c omecases, at least one R50is -CN.

[0079] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R50is independently selected fro,ses, e and . I

[0080] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is s , , ,, , h is [so e e o e s, o a co pou o sa o o ua o o ua - , is s ,, ,

[0082] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is s , [la (I-BB), X is s , .

[0084] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is s, , a [is , which is optionally substituted with one or more substituents independently seR50.

[0086] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independentlyselected from R50.

[0087] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is, which is optionally substituted with one or more substituents independently selected from R50.

[0088] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently s50.

[0089] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently s50.

[0090] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is O , which is optionally substituted with one or more substituents independently selected from R50.

[0091] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is, which is optionally substituted with one or more substituents independently selected from R50.

[0092] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is, which is optionally substituted with one or more substituents independently select

[0093] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently s50.

[0094] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently s.

[0095] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently selected from R50.

[0096] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is, which is optionally substituted with one or more substituents independently selected from R50.

[0097] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently se0.

[0098] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently se50.

[0099] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independentlyselected from R50.

[0100] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is, which is optionally substituted with one or more substituents independently selected from R50.

[0101] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently se50.

[0102] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently seR50.

[0103] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is which is optionally substituted with one or more substituents independently selected from R50.

[0104] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is, which is optionally substituted with one or more substituents independently selected from R50.

[0105] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently selected fr

[0106] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently seR50.

[0107] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently seected rom R50.

[0108] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is which is optionally substituted with one or more substituents independentlyselected from R50.

[0109] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is, which is optionally substituted with one or more substituents independently selected from R50

[0110] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is O N , which is optionally substituted with one or more substituents independently s R50.

[0111] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently sR50.

[0112] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is , which is optionally substituted with one or more substituents independently se ected rom R50.

[0113] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is which is optionally substituted with one or more substituents independentlyselected from R50.

[0114] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is, which is optionally substituted with one or more substituents independently selected from R50.

[0115] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is s , ,,, ,,,rom ,

[0116] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is.

[0117] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is . [0ome embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is . [0me embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is .

[0120] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is

[0121] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is

[0122] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is . [0me embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is . [0me embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is .

[0125] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is .

[0126] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is.

[0127] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is.

[0128] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is s , , H , and ntly s

[0129] In some embodiments, for a compound or salt of Formula (I) or Formula (I-BB), X is s, each of which is optionally substituted with one or more substituents independently selected from R50. [0013Formula (I-A), or a pharmaceutically acc

[0131] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), A is selected from an optionally substituted 5- to 15-membered heterocycle. In some cases, A is selected from an optionally substituted 5- to 12-membered heterocycle. In some cases, A is selected from an optionally substituted 5- to 13-membered heterocycle. In some cases, A is selected from an optionally substituted 5- to 10-membered heterocycle. In some cases, A is selected from an optionally substituted 10- to 13-membered heterocycle. In some cases, A is selected from an optionally substituted 5- to 9-membered heterocycle. In some cases, A is selected from an optionally substituted 5- to 8-membered heterocycle. In some cases, A is selected from an optionally substituted 5- to 7-membered heterocycle. In some cases, A is selected from an optionally substituted 5- to 6-membered heterocycle. In some cases, A is selected from an optionally substituted 5-membered heterocycle. In some cases, A is selected from an optionally substituted 6-membered heterocycle. In some cases, A is selected from an optionally substituted 7-membered heterocycle. In some cases, A is selected from an optionally substituted 8-membered heterocycle. In some cases, A is selected from an optionally substituted 10-membered heterocycle. In some cases, A is selected from an optionally substituted 11-membered heterocycle. In some cases, A is selected from an optionally substituted 12-membered heterocycle. In some cases, A is selected from an optionally substituted 13- membered heterocycle. In some cases, the heterocycle of A has at least one nitrogen atom. In some cases, the heterocycle of A has one or two nitrogen atoms. In some cases, the heterocycle of A has one nitrogen atom. In some cases, the heterocycle of A has at least two nitrogen atoms. In some cases, the heterocycle of A has two nitrogen atoms. In some cases, the heterocycle of A has at most two nitrogen atoms. In some cases, the heterocycle of A does not include a nitrogen atom. In some cases, the heterocycle of A has at least one oxygen atom. In some cases, the heterocycle of A has one or two oxygen atoms. In some cases, the heterocycle of A has one oxygen atom. In some cases, the heterocycle of A has two oxygen atoms. In some cases, the heterocycle of A has at most one oxygen atom. In some cases, the heterocycle of A has at most two oxygen atoms. In some cases, the heterocycle of A has at least one sulfur atom. In some cases, the heterocycle of A has one or two sulfur atoms In some cases the heterocycle of A has one sulfur atom In some cases theheterocycle of A has two sulfur atoms. In some cases, the heterocycle of A has at most one sulfur atom. In some cases, the heterocycle of A has at most two sulfur atoms. In some cases, the heterocycle of A has one nitrogen atom and one oxygen atom. In some cases, the heterocycle of A has one nitrogen atom and one sulfur atom. In some cases, the heterocycle of A has one oxygen atom and one sulfur atom. In some cases, the heterocycle of A has two nitrogen atoms and one oxygen atom. In some cases, the heterocycle of A has two nitrogen atoms and one sulfur atom. In some cases, the heterocycle of A has one nitrogen atom, one sulfur atom, and one oxygen atom. In some cases, the heterocycle of A is bicyclic or tricyclic. In some cases, the heterocycle of A is bicyclic. In some cases, the heterocycle of A is tricyclic. In some cases, the heterocycle of A is a fused heterocycle. In some cases, the heterocycle of A is a bridged heterocycle. In some cases, the heterocycle of A is a bridged heterocycle and fused heterocycle. In some cases, A is selected from h is oome cases, A is selected from , each of which is optionally substituted with one or more substituents ndependent y se ected rom R50. In some cases, A is selected from , ,optionally substituted with one or more substituents independently selected from R50. In some c ,, ents i ,, each of which is optionally substituted with one ofrom R50. In some cases, A is selected from h of wc s optona y substtuted wt one or more substtuents ndependenty seected rom . In some cases, A is selected from , each of which isoptionally substituted with one or more substituents independently selected from R50. In some cases, A is, which is optionally substituted with one or more substituents independently selected from R50. In some cases,, which is optionally substituted with one or moresubstituents independently selected from R50. In some case , which is optionally substituted with one or more substituents independently se . In some cases, A is a bridged heterocycle.

[0132] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), A is selected from 9- to 14-membered heterocycle, wherein the 9- to 14-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

[0133] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), A is selected from 9- to 13-membered heterocycle, wherein the 9- to 13-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

[0134] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), A is selected from 9- to 12-membered heterocycle, wherein the 9- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

[0135] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), A is selected from 9-membered heterocycle, wherein the 9-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

[0136] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), A is selected from 10-membered heterocycle, wherein the 10- membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

[0137] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), A is selected from 11-membered heterocycle, wherein the 11- membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

[0138] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), A is selected from 12-membered heterocycle, wherein the 12- membered heterocycle is optionally substituted with one or more substituents independently selected from R50

[0139] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), A is selected from 13-membered heterocycle, wherein the 13- membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

[0140] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), A is selected from 14-membered heterocycle, wherein the 14- membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

[0141] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), the heterocycle of A has at least one heteroatom selected from nitrogen.

[0142] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), the heterocycle of A has at least one heteroatom selected from sulfur.

[0143] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), the heterocycle of A has at least one heteroatom selected from oxygen.

[0144] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), the heterocycle of A has at least one heteroatom selected from nitrogen, sulfur, and oxygen.

[0145] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), the heterocycle of A is a fused heterocycle.

[0146] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), the heterocycle of A is a bridged heterocycle.

[0147] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), the heterocycle of A is a bridged heterocycle and a fused heterocycle.

[0148] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), the heterocycle of A has at least one oxygen atom.

[0149] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), the heterocycle of A has at least one nitrogen atom.

[0150] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), the heterocycle of A has 3 heteroatoms.

[0151] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), A and the atoms to which it is bound is selected from an optionally substituted 5- to 15-membered heterocycle ).

[0152] In some embodiments, for a com f Formula (I), Formula (I-A), Formula(I-AA), or Formula (I-BB), each R50is independently selected from -CN, =O, C1-6 alkyl, -C(O)R20, -C(O)N(R20)2, 5- to 6-membered heterocycle, wherein the C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3- C5 carbocycle and 5- to 6-membered heterocycle are each optionally substituted independently with one or more R1*. In some cases, each R1*is independently selected from halogen, -OR20, - N(R20)2, =O, -CN, -NHCN, 5- to 6-membered heterocycle and C3-C6carbocycle, wherein the 5- to 6-membered heterocycle and C3-C12carbocycle are each optionally substituted independently with one or more R2*. In some cases, each R2*is independently selected from halogen, -OR20, -N(R20)2, -C(O)OR20, C1-6 hydroxyalkyl. In some cases, each R50is independently selected from -CN, =O, C1-6alkyl, -C(O)R20, -C(O)N(R20)2, 5- to 6-membered heterocycle, wherein the C1-6alkyl and 5- to 6-membered heterocycle are each optionally substituted independently with one or more R1*, wherein each R1*is independently selected from halogen, -OR20, -N(R20)2, =O, -CN, -NHCN, 5- to 6-membered heterocycle and C3-C6carbocycle, wherein the 5- to 6-membered heterocycle and C3-C6 carbocycle are each optionally substituted independently with one or more R2*, wherein each R2*is independently selected from halogen, -OR20, -N(R20)2, -C(O)OR20, C1-6 hydroxyalkyl. In some cases, each R50is independently selected from -CN, =O, C1-3alkyl, -C(O)R20, -C(O)N(R20)2, 5- to 6-membered heterocycle, wherein the C1-3alkyl and 5- to 6-membered heterocycle are each optionally substituted independently with one or more R1*, wherein each R1*is independently selected from halogen, -OR20, -N(R20)2, =O, -CN, -NHCN, 5- to 6-membered heterocycle and C3- C6carbocycle, wherein the 5- to 6-membered heterocycle and C3-C6carbocycle are each optionally substituted independently with one or more R2*, wherein each R2*is independently selected from halogen, -OR20, -N(R20)2, -C(O)OR20, C1-3 hydroxyalkyl. In some cases, each R20is selected from hydrogen and C1-3alkyl. In some cases, each R50is independently selected from -CH3, =O, -CN,,, . In s ,n some cases, each R50is independently selected from, and

[0153] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), A is selected from ,, , , ,,, , , , , and. In some cases, A is selected from ,, , , A is s,, , , , romomec A is [B is selected from an 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituents independently selected from halogen, -CN, - NH2, and C1-6alkyl. In some cases, B is selected from an 8-membered heterocycle, wherein the 8- membered heterocycle is substituted with one or more substituents independently selected from halogen, -CN, -NH2, and C1-6 alkyl. In some cases, the heterocycle of B has one sulfur atom and no other heteroatoms. In some cases, the heterocycle of B is an unsaturated heterocycle. In some cases, B is selected from , each of which is optionally substituted. In some cases, B isselected from , each of which is substituted with at least one substituent. In some cases, Bi ses,B. In some cases, Y is O. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1alkylene. In some cases, two substituents on the same carbon atom of L come togethcarbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle. In some cases, each L is selected from ,and . In some cases, R2is selected from optionally s es, R2is selected from optionally substituted -L-heterocycle, wherein the heterocycle is a saturated heterocycle. In some cases, the heterocycle is selected from , each of which is optionally substituted with one or more R6. In some cdently selected from halogen, hydroxy, Cl-C3 alkyl, Cl-C3 haloalkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, oxo, =NO-Cl-C3alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2,and -O-Cl-C3alkyl, wherein the alkyl of -O-Cl-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy. In some cases, each R6is independently selected from halogen, Cl-C3 alkyl, and Cl-C3 haloalkyl. In some cases, each R6is independently selected from halogen. In some cases, Y-R2is selected from 2 is

[0155] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), B and the atoms to which it is bound is selected from an 8- to 10-membered heterocyc ),wherein the 8- to 10-membered heterocycle is optionally substituted with one or more substituentsindependently selected from halogen, -CN, -NH2, and C1-6 alkyl. In some cas. . [for a compound or salt of Formula (I), or Formula (I-A), B is s ses,

[0157] In some embodiments, Formula (I) is represented by Formula (I-AA): Formula (I-AA),or a pharmaceutically acceptable salt thereof.

[0158] In some embodiments, Formula (I) is represented byFormula (I-BB), or a pharmaceutically acceptable salt;wherein C is selected from a C5-C8carbocycle and 5- to 8-membered heterocycle, wherein the C5-C8 carbocycle and 5- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -OMe, -N(R20)2, - C(O)R20, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0159] In some embodiments, for a compound or salt of Formula (I-AA) or Formula (I-BB), C is selected from a C5-C7carbocycle and 5- to 7-membered heterocycle, wherein the C5-C7carbocycle and 5- to 7-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -OMe, -N(R20)2, -C(O)R20, =O, -CN, - NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, C is selected from a 5- to 7- membered heterocycle, wherein the 5- to 7-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -OMe, -N(R20)2, - C(O)R20, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, C is selected from a 5-membered heterocycle. In some cases, C is selected from a 6-membered heterocycle. In some cases, C is selected from a 7-membered heterocycle. In some cases, C and the atoms to which it is bound is a 5-membered heterocycle ).

[0160] In some embodiments, for a compound or salt of Formula (I-AA) or Formula (I-BB), C and the atoms to which it is bound is selected from a C5-C7 carbocycle and 5- to 7-membered heterocycle, wherein the C5-C7carbocycle and 5- to 7-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -OMe, - N(R20)2, -C(O)R20, =O, -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0161] In some embodiments, for a compound or salt of Formula (I-AA) or Formula (I-BB), C i ,, each of which is optionally substituted. In some cases, C is selectedf ,each of which is optionally substituted. In some cases, C is selected fro ,, each of which is optionally substituted. In some c more substituents independently selected fromhalogen, -OH, -OMe, =O, -NH2, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl. In some cases, C is optionally substituted with one or more substituents independently selected from halogen, and C1-F 6 alkyl. In some cases, C is selected from ,, , a C is C issubstituted.

[0162] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), B is selected from an optionally substituted 7- to 15-membered fused heterocycle and optionally substituted C7C15fused carbocycle In some cases and optionally substituted C7C15fusedcarbocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle. In some cases, B is an optionally substituted unsaturated 7- to 15-membered fused heterocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heteroaryl. In some cases, B is selected from an optionally substituted 7- to 15-membered fused heteroaryl and optionally substituted C7-C15 fused aryl. In some cases, B is an optionally substituted unsaturated C7-C15 fused carbocycle. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle, wherein the fused heterocycle is partially unsaturated. In some cases, B is an optionally substituted 7- to 15-membered fused heterocycle, wherein the fused heterocycle is partially saturated.

[0163] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 fused carbocycle. In some cases, and optionally substituted C8-C15 fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted unsaturated 8- to 15-membered fused heterocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heteroaryl. In some cases, B is selected from an optionally substituted 8- to 15-membered fused heteroaryl and optionally substituted C8-C15fused aryl. In some cases, B is an optionally substituted unsaturated C8-C15fused carbocycle. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is partially unsaturated. In some cases, B is an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is partially saturated.

[0164] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), B is selected from an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is formed by combining three rings (e.g., tricyclic). In some cases, B is selected from an optionally substituted 8- to 15-membered fused heterocycle, wherein the fused heterocycle is formed by combining two rings (e.g., bicyclic). In some cases, for B the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15fused carbocycle are each independently bicyclic or tricyclic. In some cases, for B the optionally substituted 8- to 15- membered fused heterocycle is bicyclic. In some cases, for B the optionally substituted 8- to 15- membered fused heterocycle is tricyclic.

[0165] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), the heterocycle or carbocycle of B is bicyclic. In some cases, the heterocycle or carbocycle of B is tricyclic. In some cases, the tricyclic heterocycle contains three interconnected rings of atoms.

[0166] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), for B, the heterocycle and carbocycle are each independently selected from bicyclic and tricyclic. In some cases, for B, the heterocycle and carbocycle are each independently tricyclic. In some cases, for B, the heterocycle and carbocycle are each independently bicyclic.

[0167] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15 f ach ooptionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8-C15f andeach of which is optionally substituted with one or more substituents. In some cases, Bi s, B ieach of which is optionally substituted with one or more substituents. In some cases,B is selected from , each of which is optionally substituted with one or more substituents.

[0168] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), B is s ,ally s, ly substituted with one or more substituents.

[0169] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), for B, the optional substituents of the heterocycle and carbocycle are each independently selected from halogen, -CN, -NO2, =O, -N(R20)2, -B(OR20)2, -OR20, -SR20, C1-6aminoalkyl, C1-6alkoxy, C1-6alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle. In some cases, the optional substituents of the heterocycle and carbocycle are each independently selected from halogen, - CN, -NO2, =O, -N(R20)2, -B(OR20)2, -OH, -SR20, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In someindependently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, -O-Cl-C3 haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, the optional substituents of the heterocycle and carbocycle are each independently selected from halogen, -CN, =O, -NH2, -N(C1-6alkyl)H -N(C1-6alkyl)2, -OH, C1-6aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of the heterocycle and carbocycle are each independently selected from oxo, -NH2, halogen, C1-C3alkyl. In some cases, for B, the optionally substituted 8- to 15-membered fused heterocycle and optionally s ed f , ,,, ,. In some cases, B is selected fro ,,

[0170] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), B is selected from an optionally substituted 7- to 12-membered fused heterocycle and optionally substituted C9-10 fused carbocycle. In some cases, the heterocycle of B has at least one sulfur atom. In some cases, the heterocycle of B has one or sulfur atoms. In some cases, the heterocycle o ach ore independently selected at each occurrence from halogen, C1-C3 alkyl, -B(OR20)2, -OR20, - C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OH, - N ,

[0171] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), B is selected from an optionally substituted 8- to 10-membered fused heterocycle having at least one sulfur, each of which is optionally substituted. In some cases, the one or more optional s ts of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -OR20,-C(O)N(R20)2, -N(R20)2, =O, -CN, -NHCN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6haloalkyl, C2-6alkenyl, and C2-6alkynyl. In some cases, the one or more optional substituents of B are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted. In some cases, B is substituted with at least one -NH2. In some cases, B is selected from andsome cases, B is substituted with at least one -NH2at least one -CN. In some cases,B .

[0172] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), B is an optionally substituted 7- to 11-membered fused heterocycle. In some cases, B is an optionally substituted 8- to 10-membered fused heterocycle. In some cases, B is an optionally substituted 7- membered fused heterocycle. In some cases, B is an optionally substituted 8-membered fused heterocycle. In some cases, B is an optionally substituted 9-membered fused heterocycle. In some cases, B is an optionally substituted 10-membered fused heterocycle. In some cases, the heterocycle of B is an unsaturated heterocycle. In some cases, the heterocycle of B is a non- aromatic heterocycle. In some cases, B has at least one sulfur atom. In some cases, B has at two sulfur atoms. In some cases, B has at least one sulfur atom and at least one nitrogen atom. In some cases, B has at least one sulfur atom and at least one oxygen atom. In some cases, B has only 1 S heteroatom. In some cases, B has at least 2 heteroatoms. In some cases, B is selected fromSS , ,each of which is optionally substituted. In some cases, B is selected froma each of which is optionally substituted. In some cases, B is selected fr ,, each of which is optionallysubstituted. In some cases, B is selected fro , each of which is optionally substituted. In some cases, the one or more optional substtuents of B, are independently selected at each occurrence from halogen, oxo, -NH2, C1-C3alkyl, -B(OH)2, -OH, -O-Cl-C3haloalkyl, -C(O)NH2, -NH2, =O, -CN, C1-6 alkoxy, C1-6 hydroxyalkyl, and C2-6 alkynyl. In some cases, the one or more optional substituents of B, are independently selected at each occurrence from halogen, C1-C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least three substituents. In some cases, B is substituted with at least two substituents. In some cases, B is substituted with at least one substituent. In some cases, B is substituted with at least one substituent selected from halogen, C1- C3 alkyl, -NH2, and -CN. In some cases, B is substituted with at least one substituent selected from halogen. In some cases, B is substituted with at least one substituent selected from -NH2. In some cases, B is substituted with at least one substituent selected from -CN. In some cases, B is selected f,, , . In s [0so e e o e s, o a co pou o sa o o u a , o o u a - , s an optionally substituted 8- to 10-membered fused carbocycle. In some cases, B is a substituted 8- to 10-membered fused carbocycle. In some cases, B is an optionally substituted 9-membered fused carbocycle. In some cases, B is a substituted 9-membered fused carbocycle. In some cases, B is which is optionally substituted with one or more substituents. In some cases, B iswhich is substituted with one or more substituents. In some cases, for B, the one ormore substituents are independently selected from halogen, oxo, -NH2, C1-C3 alkyl, -B(OH)2, - OH, -C(O)NH2, -NH2, =O, -CN, C1-6alkoxy, C1-6hydroxyalkyl, and C2-6alkynyl. In some cases, B is substituted with at least one halogen. In some cases, B is substituted with at least one chlorine. In some cases, B is substituted with at least one fluorine. In some cases, B is selectedf entsselected from halogen and C1-6 haloalkyl. In some case , which is substituted withone or more substituents selected from halogen. In some cases, B is selected fr ,, wc s subst tuted w t one or more subst tuents se ected rom uor ne. n some cases, B is s h issubstituted with one or more substituents selected from chlorine. In some cases, B is selected f.

[0174] In some embodiments, for a compound or salt of Formula (I), or Formula (I-A), B is selected from an 8- to 10-membered heterocycle, wherein the 8- to 10-membered heterocycle isoptionally substituted with one or more substituents independently selected from halogen, -CN, - NH2, and C1-6alkyl. In some cases, the heterocycle of B is selected fro, ,, each of which is optionally substituted with o m halogen, -CN, -NH2, and C1-6 alkyl. In somecases, B is selected from , ,.

[00175] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), Y is -O-. In some cases, Y is a bond. In some cases, Y is -S-. In some cases, Y is -N(R5)-.

[0176] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), L is selected from C1-C4 alkylene. In some cases, L is selected from an unsubstituted C1-C4alkylene. In some cases, L is selected from an unsubstituted C1alkylene. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle. In some cases, two substituents on the same carbon atom of L come together to form a C3-C6carbocycle.

[0177] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AAunsubstituted C1-C4alkylene. In some cases, each L is independently selected from a Cl-C4alkylene optionally substituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3- C6carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl. In some cases, the optional substituents of L are selected from Cl-C4 hydroxyalkyl, Cl-C4alkyl, C3-C6carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6haloalkyl. In some cases, L is selected f and ,. In some cases, each L is independently selected from a substituted C, wo substituents on the same carbon atom of L come together to form a C3-C6 carbocycle 3- to 5-membered heterocycle. In some cases, each L is independently selected from a substituted C2-3alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3carbocycle or 4-membered heterocycle, wherein the C3carbocycle is optionally substituted with one or more substituents selected from halogen. In some cases, each L is independently selected from . In somecases, each L is independently selected from , and. In some cases, each L is independently selected fro. In some cases, each L is independently selected from a Cl-C4alkylene optionally substituted with one or more substituents independently selected from halogen and Cl-C4alkyl. In some cases, L is selected from.

[0178] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA) or Formula (I BB) each L is independently selected from an unsubstituted Cl C4 alkyleneIn some cases, L is selected from and . In some cases, L is selected from .

[0179] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), R2is selected from heterocycle, Cl-C6 alkyl, -L-heterocycle, -L- N(R20)2, -L-OR20, -L-aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R20)2, - L-Cl-C6haloalkyl, -L-OR20, -L-NR20C(O)-aryl, -L-COOH, -L-NR20S(O)2(R20), -L-S(O)2N(R20)2, -L-N(R20)C(O)(OR20), -L-OC(O)N(R20)2, and -L-C(=O)OCl-C6 alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of -L-NR20C(O)- aryl, the aryl portion of -L-NR20C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L- heteroaryl are each optionally substituted with one or more R7.

[0180] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), R2is selected from heterocycle, -L-heterocycle, -L-aryl, -L- heteroaryl, and -L-N(R20)2, wherein the heterocycle, the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7.

[0181] In some embodiments, for a compound or salt Formula (I), Formula (I-A), Formula (I- AA), or Formula (I-BB), R2is -L-heterocycle, wherein the heterocycle portion is optionally substituted. In some cases, R2is -L-heterocycle, wherein the heterocycle portion is a bicyclic heterocycle. In some cases, R2is -L-heterocycle, wherein the heterocycle portion is a monocyclic heterocycle. In some cases, R2is -L-heterocycle, wherein the heterocycle portion is a saturated heterocycle. In some cases, R2is selected from a -L-5- to 10-membered heterocycle. In some cases, R2is selected from a -(C1-C2 alkylene)-5- to 10-membered heterocycle. In some cases, R2is selected from a -L-5- to 8-membered heterocycle. In some cases, R2is selected from a -L-5- to 8-membered saturated heterocycle. In some cases, R2is a -L-5-membered heterocycle. In some cases, R2is a -L-8-membered heterocycle. In some cases, the heterocycle contains at least 1 nitrogen atom. In some cases, the heterocycle contains at most 1 nitrogen atom. In some cases, the heterocycle contains 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at least 1 nitrogen atom. In some cases, the bicyclic heterocycle contains at most 1 nitrogen atom. In some cases, the bicyclic heterocycle contains 1 nitrogen atom. In some cases, Y-R2is selected from, wherein the heterocycle portion isoptionally substituted. In some cases, Y-R2is selected from , wherein the heterocycle portion is optionally substituted. In some case ycle portion is optionallysubstituted with one or more substituents selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 haloalkyl, C1-C3 alkoxy, -CN, and Cl-C3 aminoalkyl. In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, Cl-C3hydroxyalkyl, Cl-C3alkyl, Cl-C3haloalkyl, C1-C3alkoxy, and Cl-C3aminoalkyl. In some cases, the heterocycle portion is optionally substituted with one or more substituents selected from C1-C3alkyl and halogen. In some cases, Y-R2is selected from 2 is s

[00182] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), R2is selected from optionally substituted -L-heterocycle. In some cases, the heterocycle is a bicyclic heterocycle. In some cases, the heterocycle is a monocyclic heterocycle. In some cases, the heterocycle has only 1 nitrogen atom. In some cases, the heterocycle has only 1 nitrogen atom and no other heteroatoms. In some cases, Y-R2is selected from , wherein the heterocycle portion is optionally substituted.In some cases, Y-R2is selected from , wherein the heterocycleportion is optionally substituted. In some cases, Y-R2is selected fro, wherein the heterocycle portion is optionally substituted. In some cases, Y-R2is selected fromheterocycle is optionally substituted with one or more substituent selected from halogen, hydroxy, Cl-C3 alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, oxo, =CH2, =NO-Cl-C3 alkyl, - CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-Cl-C3 alkyl, wherein the alkyl of -O-Cl-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo, a ,, rom. [0, , , mula (I-AA), or Formula (I-BB), R2is -L-heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7. In some cases, the heteroaryl is selected from a 5- to 6- membered heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7. In some cases, the heteroaryl is selected from a 5-membered heteroaryl, wherein the heteroaryl portion is optionally substituted with one or more R7. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has two nitrogen atoms. In some cases, the heteroaryl has three nitrogen atoms. In some cases, the heteroaryl is selected from l is cases, Y-R2is selected from and, wherein the heteroaryl portion is optionally sub7stituted with one or more R . In some cases, each R7is independently selected from Cl-C4alkyl, halogen, and Cl-C4haloalkyl. In some cases Y R2is selected fromIn some cases YR om [), Formula (I-AA), or Formula (I-BB),R2is -L-aryl, optionally substituted with one or more R7. In some cases, wherein Y-R2is selected from , wherein the heterocycle portion is optionallysubstituted with one or more R7. In some cases, Y-R2is selected fro and.

[0185] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), R2is -L-N(R20)2. In some cases, Y-R2is selected from .

[0186] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), R2is heterocycle, optionally substituted with one or more R6. In somecases, the heterocycle , which is optionally substituted. In some cases, theheterocycle of R2is , In some cases, Y-R2is .

[0187] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), R2is selected from heterocycle, -L-heterocycle, wherein the heterocycle, and the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6; -L-aryl, and -L-heteroaryl, wherein the aryl of the -L-aryl, and the heteroaryl of - L-heteroaryl are each optionally substituted with one or more R7; and -L-N(R20)2. In some cases, the heterocycle of R2is selected from ,2 is octed from , , and , wherein the aryl and the heteroaryl are each optionallysubstituted with one or more R7; and . In some cases, the heterocycle of R2iss , theheterocycle is optionally substituted with one or more R6; wherein the aryl and heteroaryl of R2is selected from, wherein the aryl and the heteroaryl are each optionally substituted with one or more R7; a. In some cases, each R6is independently selected from halogen, hydroxy, Cl-C3alkyl, Cl-C3haloalkyl, - N(R5)CH2heterocycle, -CH2OC(O)N(R5)2,and -O-Cl-C3alkyl, wherein the alkyl of -O-Cl-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy; and wherein each R7is selected from Cl-C3 alkyl, halogen and Cl-C3 haloalkyl. In some cases, the heterocycle of R2, the aryl and heteroaryl of R2, and -N(R20)2 of R2is selected fro ,, , In s,, wherein the heterocycle, and the h y substituted with one or more R6;and, wherein the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are eachoptionally substituted with one or more R7; an ,, , ,, , , ,2is s , ,, [0 (I-A), Formula(I-AA), or Formula (I-BB), L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from hydroxy, Cl-C4 hydroxyalkyl and Cl-C4alkyl. In some cases, L is independently selected from a Cl-C4alkylene optionally substituted with one or more substituents independently selected from Cl-C4 alkyl. In some cases, L is selected from C1-C4 alkylene. In some cases, L is selected from C1-C2 alkylene. In some cases, L is . In some cases, L i .

[0189] In some embod ments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB),each L is independently selected from an optionally substituted Cl-C4 alkylene; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle, wherein the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6haloalkyl. In some cases, the optional substituents of L are selected from Cl-C4hydroxyalkyl, Cl-C4alkyl, C3-C6carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6haloalkyl.

[0190] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each L is independently selected from a substituted Cl-C4 alkylene, wherein two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some cases, the C3-C6 carbocycle is optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 haloalkyl.

[0191] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each L is independently selected from a substituted Cl-C4 alkylene, and two substituents on the same carbon atom of L come together to form a C3-C6carbocycle. In some casessubstituents on the same carbon atom of L come together to form a C3carbocycle. In some cases, each L is independently selected from .

[0192] In some embodiments, foror salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), R2is selected from -L-heterocycle, wherein the heterocycle portion of -L-heterocycle is optionally substituted with one or more R6. In some cases, the heterocycle is a saturated heterocycle. In some cases, the heterocycle has at least one nitrogen atom and at least one sulfur atom. In some cases, the heterocycle has at least one nitrogen atom. In some cases, the heterocycle has at least one sulfur atom.

[0193] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), R2is selected from , wherein the heterocycle portion is optionally substitut

[0194] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), Y-R2is selected fro , wherein the heterocycle portion is optionally substituted with.

[0195] In some embodiments, for a compound or salt Formula (I), Formula (I-A), Formula (I- AA), or Formula (I-BB), Y-R2is selected from and, wherein the heterocycle portion is optionally substituted with one or moreR6.

[0196] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), Y-R2is selected from ,, wherein the heterocycle portion is optionally substituted with one or more R6.

[0197] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AAheterocycle portion of the -L-saturated heterocycle is optionally substituted with one or more R6, and contains one nitrogen atom and one sulfur atom. In some cases, Y-R2is selected from , wherein the heterocycle portion is optionallysubstituted with one or more R6. In some cases, Y-R2is selected from ,, wherein the heterocycle portion is optionally substituted with o from C1-C3 alkyl and oxo. In some cases, Y-R2is selected fromrom [so e e o e s, o a co pou o sa o o u a , o u a - , o mula (I-AA), or Formula (I-BB), Y is a bond. In some cases, R2is selected from an optionally substituted heteroaryl and optionally substituted aryl. In some cases, R2is selected from an optionally substituted heteroaryl. In some cases, the heteroaryl has at least one nitrogen atom. In some cases, the heteroaryl has at least two nitrogen atoms. In some cases, the heteroaryl only contain nitrogen atom(s). In some cases, the heteroaryl is a 6-membered heteroaryl. In some cases, the heteroaryl is a 5-membered heteroaryl. In some cases, the heteroaryl is selected from , , and N , each of which is optionally substituted. In some cases, the heteroaryl is selected fro, N each of which is optionally substituted. In some cases, R2is selectedfrom an optionally substituted aryl. In some cases, the aryl is a phenyl. In some cases, the heteroaryl is optionally substituted with one or more R6, wherein each R6is selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 haloalkyl, C1-C3 alkoxy, cyano, -CH2heterocycle, -C1-C3 alkyl-N(R5)2, and -C(O)N(R5)2. In some cases, R6is selected from Cl-C3alkyl, -CH2heterocycle, and -C(O)N(R5)2. In some cases, the aryl is optionally substituted with one or more R7. In someN N c , N N , [ula (I-AA), or Formula (I-BB), each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3alkyl, oxo, Cl-C3haloalkyl, C1-C3alkoxy, cyano, =CH2, =NO-Cl-C3alkyl, Cl- C3aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3 alkoxy)Cl-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Cl-C3alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, - CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, - OC(O)N(R5)2, -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl)phenyl, - OC(O)heterocycle, -O-Cl-C3alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), - NR20S(O)2R20, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1- C3alkyl)(Cl-C3alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Cl-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

[0200] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R6is independently selected from halogen, -OH, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 haloalkyl, C1-C3 alkoxy, -CN, Cl-C3 aminoalkyl, -Q-phenyl, -Q- phenylSO2F, -NHC(O)phenyl, -NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, -N(R5)2, (C1-C3alkoxy)Cl-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3haloalkyl)C(=O)-, -SO2F, (C1-C3alkoxy)Cl-C3 alkoxy, -CH2OC(O)N(R5)2, -CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, - CH2NHC(O)C1-C6alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, - OC(O)N(R5)2-OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl) -OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl)phenyl(C1-C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl)phenyl, - OC(O)heterocycle, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and - OC(O)NH(C1-C3 alkyl)(Cl-C3 alkyl)phenyl are each optionally substituted with -C(O)H and OH, and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

[0201] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R6is independently selected from halogen, hydroxy, Cl-C3 alkyl, Cl-C3haloalkyl, oxo, C1-C3alkoxy, Cl-C3hydroxyalkyl, (C1-C3alkoxy)Cl-C3alkyl-, =CH2, =CF2, -OC(O)N(R5)2, =NO-Cl-C3 alkyl, -N(R5)S(O)2(R5), -CH2OC(O)N(R5)2, -CH2OC(O)heterocycle, - (CH2)0-1S-heterocycle, -(CH2)0-1-O-heterocycle, and -O-Cl-C3 alkyl, wherein the alkyl of -O-Cl-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy, and wherein the heterocycle of -(CH2)0-1-O-heterocycle and -(CH2)0-1-S-heterocycle are each optionally substituted with one or more substituents selected from C1-6 alkyl, C1-6 haloalkyl, C1-6 alkyl-OR20, and -OR20.

[0202] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R6is independently selected from halogen, -OH, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, Cl-C3 haloalkyl, C1-C3 alkoxy, -CN, and Cl-C3 aminoalkyl. In some cases, each R6is independently selected from halogen, Cl-C3alkyl, and Cl-C3haloalkyl.

[0203] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R6is independently selected from halogen, -OH, Cl-C3 hydroxyalkyl, Cl-C3alkyl, Cl-C3aminoalkyl, Cl-C3haloalkyl, C1-C3alkoxy, -N(R5)2, and oxo. In some cases, each R6is independently selected from -OH, Cl-C3hydroxyalkyl, Cl-C3alkyl, Cl-C3aminoalkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, each R6is independently selected from Cl- C3 alkyl, C1-C3 alkoxy, and -N(R5)2. In some cases, each R6is independently selected from halogen, hydroxy, Cl-C3alkyl, Cl-C3haloalkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, oxo, =NO- Cl-C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2, and -O-Cl-C3 alkyl, wherein the alkyl of -O-Cl-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy; and wherein each R7is selected from Cl-C3alkyl, halogen and Cl- C3 haloalkyl.

[0204] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), R6is selected from halogen, -OH, Cl-C3hydroxyalkyl, Cl-C3alkyl, Cl- C3haloalkyl, C1-C3alkoxy, -CN, and Cl-C3aminoalkyl. In some cases, R6is selected from halogen and Cl-C3 alkyl. In some cases, R6is halogen. In some cases, R6is Cl-C3 alkyl. In some cases, R6is selected from halogen and Cl-C3 alkyl. In some cases, R6is selected from methyl and fluorine.

[0205] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula ( , , , , ,

[0206] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), R2is selected from .

[0207] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), Y-R2is selected from and.

[0208] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), Y-R2is selected froma . [diments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula .

[0210] In some et of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), L is selected from unsubstituted C1-C4 alkylene.

[0211] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), Y-R2is selected fro , wherein the heterocycle portion is optionally substituted with one or more R6.

[0212] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), R6of R2is independently selected at each occurrence from halogen, hydroxy, Cl-C3hydroxyalkyl, Cl-C3alkyl, Cl-C3haloalkyl, C1-C3alkoxy, cyano, and Cl-C3aminoalkyl.

[0213] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), R6of R2is independently selected at each occurrence from C1-C3alkyl and halogen.

[0214] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), Y-R2is selected from .

[0215] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), Y-R2is selected from,, ,,,, , ,,, , , , ,, [0, B), X is selected from -L- heterocycle, wubstituted; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl. In some cases, each L is independently selected fro ,,from2. In some cases, the heterocycle of L-heterocycle of R is selected fromR6. In some cases, the heterocycle of L-heterocycle of R2is . In some cases, Y-R2isselected from In some cases, Y-R2is. In some cases, Y-R2is selected fro . [mbodiments, for a compound or salt o, Formula (I-A), Formula (I-AA), or Formula (I-BB), A is selected from In some cases, Y-R .

[00218] In some embodiments, a compound or salt of Formula (I) or Formula (I-A), , wherein C is selected from a C5-C8 carbocycle and 5-o - e e e e e ocyc e, w e e e C5-C8 carbocycle and 5- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -OMe, -N(R20)2, -C(O)R20, =O, -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0219] In some embodiments, a compound or salt of Formula (I) or Formula (I-A), B is represented, wherein C is selected from a C5-C8carbocycle and 5- to 8- membered heterocycle, wherein the C5-C8 carbocycle and 5- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen -OH -OMe, -N(R20)2, -C(O)R20, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

[0220] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), n is selected from 0 to 4. In some cases, n is selected from 0 to 3. In some cases, n is selected from 0 to 2. In some cases, n is selected from 0 and 1. In some cases, n is 0. In some cases, n is 1. In some cases, n is 2.

[0221] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C2-6 alkynyl, C1-6 cyanoalkyl, and C1-6 haloalkyl. In some cases, R4is independently selected from halogen, =O, -CN, C1-6cyanoalkyl, C2-6alkynyl, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, and C1-6haloalkyl. In some cases, R4is independently selected from halogen, =O, -CN, C1-6 cyanoalkyl, C2-6 alkynyl, and C1-6 haloalkyl. In some cases, R4is independently selected from -CN, C1-6 cyanoalkyl, and C2-6 alkynyl. In some cases, each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6cyanoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl.

[0222] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), Q is a bond. In some cases, Q is a S. In some cases, Q is a O.

[0223] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R7is independently selected from halogen, hydroxy, HC(=O)-, Cl-C4alkyl, Cl-C4alkoxy, Cl-C4haloalkyl, Cl-C4hydroxyalkyl, and -N(R5)2. In some cases, each R7is independently selected from halogen, hydroxy, Cl-C4alkyl, Cl-C4alkoxy, Cl-C4haloalkyl, and Cl-C4 hydroxyalkyl.

[0224] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), Y is -O-. In some cases, each L is independently selected from a Cl-C4alkylene optionally substituted with one or more substituents independently selected from halogen, and Cl-C4 alkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 4- to 6-membered heterocycle, wherein the C3-C6carbocycle and 3- to 6-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen. In some cases, each L ,. In sa , , [ula (I-AA), or Formula (I-BB),Y-R2is selected from ,, ,

[0226] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R20is independently selected from hydrogen; and C1-6 alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle In some cases each R20is independently selected from hydrogen and C1 6alkyl Insome cases, each R20is independently selected from C1-6alkyl. In some cases, each R20is independently selected from hydrogen.

[0227] In some embodiments, for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), each R20is independently selected from hydrogen; and C1-6alkyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, and =NH. In some cases, each R20is independently selected from hydrogen; and unsubstituted C1-6 alkyl, and 3- to 12-membered heterocycle which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, and =NH.

[0228] In some embodiments, for a compound or salt of Formula (I) or Formula (I-A), each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen; and C1-6alkyl, C3-12carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen; and C1-6alkyl, C3-6carbocycle, and 3- to 6-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NH2, -N(C1-6 alkyl)2, C1-10 alkyl, - C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle. In some cases, each R21is independently selected from hydrogen; and C1-6 alkyl, C3-6 carbocycle. In some cases, each R21is independently selected from hydrogen and C1-6 alkyl.

[0229] In some embodiments, a compound or salt of Formula (I), Formula (I-A), Formula (I- AA), or Formula (I-BB), does not contain an electrophile moiety.

[0230] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

[0231] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds or salts of Formula (I), are intended to include all Z-, E- and tautomeric forms as well.

[0232] “Isomers” are different compounds that have the same molecular formula. “Stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Certain compounds described herein contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, the asymmetric centers of which can be defined, in terms of absolute stereochemistry, as (R)- or (S)-. The present chemical entities, pharmaceutical compositions and methods are meant to include all such possible stereoisomers, including racemic mixtures, optically pure forms, mixtures of diastereomers and intermediate mixtures. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0233] The compounds or salts for Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. The compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. Separation of stereoisomers may be performed by chromatography or by forming diastereomers and separating by recrystallization or chromatography or any combination thereof (Jean JacquesAndre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0234] A "tautomer" refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. In certain embodiments, the compounds or salts for a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers may exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some non–limiting examples of tautomeric equilibrium include:

[0235] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e.g., enriched in the content of2H,3H,11C,13C and / or14C. In one particular embodiment, the compound is deuterated in at least one position. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos.5,846,514 and 6,334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0236] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms Forexample, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0237] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H,11C,13C,14C,15C,12N,13N,15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35Cl,37Cl,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0238] In certain embodiments, the compounds disclosed herein have some or all of the1H atoms replaced with2H atoms. The methods of synthesis for deuterium-containing compound are known in the art and include, by way of non-limiting example only, the following synthetic methods.

[0239] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Rajender S. The Synthesis of Radiolabeled Compounds via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32.

[0240] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0241] Compounds of the present invention also include crystalline and amorphous forms of those compounds, pharmaceutically acceptable salts, and active metabolites of these compounds having the same type of activity, including, for example, polymorphs, pseudopolymorphs, solvates, hydrates, unsolvated polymorphs (including anhydrates), conformational polymorphs, and amorphous forms of the compounds, as well as mixtures thereof.

[0242] The compounds described herein may in some cases exist as diastereomers, enantiomers, or other stereoisomeric forms. Where absolute stereochemistry is not specified, the compounds presented herein include all diastereomeric, enantiomeric, and epimeric forms as well as the appropriate mixtures thereof. Separation of stereoisomers may be performed by chromatography or bycombination thereof. (Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981, herein incorporated by reference for this disclosure). Stereoisomers may also be obtained by stereoselective synthesis.

[0243] The methods and compositions described herein include the use of amorphous forms as well as crystalline forms (also known as polymorphs). The compounds described herein may be in the form of pharmaceutically acceptable salts. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0244] In certain embodiments, compounds or salts of the compounds may be prodrugs, e.g., wherein a hydroxyl in the parent compound is presented as an ester or a carbonate, or carboxylic acid present in the parent compound is presented as an ester. The term “prodrug” is intended to encompass compounds which, under physiologic conditions, are converted into pharmaceutical agents of the present disclosure. One method for making a prodrug is to include one or more selected moieties which are hydrolyzed under physiologic conditions to reveal the desired molecule. In other embodiments, the prodrug is converted by an enzymatic activity of the host animal such as specific target cells in the host animal. For example, esters or carbonates (e.g., esters or carbonates of alcohols or carboxylic acids and esters of phosphonic acids) are preferred prodrugs of the present disclosure.

[0245] Prodrug forms of the herein described compounds, wherein the prodrug is metabolized in vivo to produce a compound as set forth herein are included within the scope of the claims. In some cases, some of the herein-described compounds may be a prodrug for another derivative or active compound.

[0246] Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. Prodrugs may help enhance the cell permeability of a compound relative to the parent drug. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. Prodrugs may be designed as reversible drug derivatives, for use as modifiers to enhance drug transport to site-specific tissues or to increase drug residence inside of a cell.

[0247] In some embodiments, the design of a prodrug increases the lipophilicity of the pharmaceutical agent. In some embodiments, the design of a prodrug increases the effective water solubility. See, e.g., Fedorak et al., Am. J. Physiol., 269:G210-218 (1995); McLoed et al., Gastrand H. Bundgaard, Int. J. Pharmaceutics, 37, 87 (1987); J. Larsen et al., Int. J. Pharmaceutics, 47, 103 (1988); Sinkula et al., J. Pharm. Sci., 64:181-210 (1975); T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series; and Edward B. Roche, Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, all incorporated herein for such disclosure). According to another embodiment, the present disclosure provides methods of producing the above-defined compounds. The compounds may be synthesized using conventional techniques. Advantageously, these compounds are conveniently synthesized from readily available starting materials.

[0248] Synthetic chemistry transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser’s Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995). Pharmaceutical Formulations

[0249] Provided herein, in certain embodiments, are pharmaceutical compositions comprising a therapeutically effective amount of any compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB) (also referred to herein as “a pharmaceutical agent”).

[0250] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0251] The compositions and methods of the present disclosure may be utilized to treat an individual in need thereof. In certain embodiments, the individual is a mammal such as a human, or a non-human mammal. When administered to an animal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for examvehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. In a preferred embodiment, when such pharmaceutical compositions are for human administration, particularly for invasive routes of administration, e.g., routes, such as injection or implantation, that circumvent transport or diffusion through an epithelial barrier, the aqueous solution is pyrogen-free, or substantially pyrogen-free. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like. The composition can also be present in a transdermal delivery system, e.g., a skin patch. The composition can also be present in a solution suitable for topical administration, such as an eye drop.

[0252] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition. The preparation or pharmaceutical composition can be a self emulsifying drug delivery system or a self microemulsifying drug delivery system. The pharmaceutical composition (preparation) also can be a liposome or other polymer matrix, which can have incorporated therein, for example, a compound of the invention. Liposomes, for example, which comprise phospholipids or other lipids, are nontoxic, physiologically acceptable and metabolizable carriers that are relatively simple to make and administer.

[0253] A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally, for example, drenches as in aqueous or non-aqueous solutions or suspensions, tablets, capsules, including sprinkle capsules and gelatin capsules, boluses, powders, granules, pastes for application to the tongue; absorption through the oral mucosa, e.g., sublingually; anally, rectally or vaginally, for example, as a pessary, cream or foam; parenterally, including intramuscularly, intravenously, subcutaneously or intrathecally as, for example, a sterile solution or suspension; nasally; intraperitoneally; subcutaneously; transdermally, for example, as a patch applied to the skin; and topically, for example, as a cream, ointment or spray applied to the skin, or as an eye drop. The compound may also be formulated for inhalation. In certain embodiments, a compound may be simply dissolved or suspended in sterile water.

[0254] A pharmaceutical composition may be a sterile aqueous or non-aqueous solution, suspension or emulsion, e.g., a microemulsion. The excipients described herein are examples and are in no way limiting. An effective amount or therapeutically effective amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect.

[0255] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and / or in the urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.

[0256] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. Pharmaceutical compositions may be administered in a manner appropriate to the disease to be treated as determined by persons skilled in the medical arts. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. Optimal doses of an agent may generally be determined using experimental models and / or clinical trials. The optimal dose may depend upon the body mass, weight, or blood volume of the subject. The use of the minimum dose that is sufficient to provide effective therapy is usually preferred. Design and execution of pre-clinical and clinical studies for a pharmaceutical agent, including when administered for prophylactic benefit, described herein are well within the skill of a person skilled in the relevant art. When two or more pharmaceutical agents are administered to treat a disease or disorder, the optimal dose of each pharmaceutical agent may be different, such as less than when either agent is administered alone as a single agent therapy. In certain particular embodiments, two pharmaceutical agents in combination may act synergistically or additively, and either agent may be used in a lesser amount than if administered alone. An amount of a pharmaceutical agent that may be adminbetween about 0.1 to 1 mg / kg, between about 1 to 10 mg / kg, between about 10-50 mg / kg, between about 50-100 mg / kg body weight. In other embodiments, the amount of a pharmaceutical agent that may be administered per day is between about 0.01 mg / kg and 1000 mg / kg, between about 100-500 mg / kg, or between about 500-1000 mg / kg body weight. The optimal dose, per day or per course of treatment, may be different for the disease or disorder to be treated and may also vary with the administrative route and therapeutic regimen.

[0257] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated in a manner appropriate for the delivery method by using techniques routinely practiced in the art. The composition may be in the form of a solid, e.g., tablet, capsule, semi-solid, e.g., gel, liquid, or gas, e.g., aerosol. In other embodiments, the pharmaceutical composition is administered as a bolus infusion.

[0258] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5thEd., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the type of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s). Alternatively, compositions described herein may be formulated as a lyophilizate. A composition described herein may be lyophilized or otherwise formulated as a lyophilized product using one or more appropriate excipient solutions for solubilizing and / or diluting the pharmaceutical agent(s) of the composition upon administration. In other embodiments, the pharmaceutical agent may be encapsulated within liposomes using technology known and practiced in the art. In certain particular embodiments, a pharmaceutical agent is not formulated within liposomes for application to a stent that is used for treating highly, though not totally, occluded arteries. Pharmaceutical compositions may be formulated for any appropriate manner of administration described herein and in the art.

[0259] A pharmaceutical composition, e.g., for oral administration or for injection, infusion, subcutaneous delivery, intramuscular delivery, intraperitoneal delivery or other method, may be in the form of a liquid. A liquid pharmaceutical composition may include, for example, one or more of the following: a sterile diluent such as water, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils that may serve as the solvent or suspending medium polyethylene glycols glycerin propylene glycol or other solvents;antibacterial agents; antioxidants; chelating agents; buffers and agents for the adjustment of tonicity such as sodium chloride or dextrose. A parenteral composition can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic. The use of physiological saline is preferred, and an injectable pharmaceutical composition is preferably sterile. In another embodiment, for treatment of an ophthalmological condition or disease, a liquid pharmaceutical composition may be applied to the eye in the form of eye drops. A liquid pharmaceutical composition may be delivered orally.

[0260] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent to provide for protection of the compound from low pH of the gastric environment and / or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and / or with an enteric coating.

[0261] A pharmaceutical composition comprising any one of the pharmaceutical agents described herein may be formulated for sustained or slow release, also called timed release or controlled release. Such compositions may generally be prepared using well known technology and administered by, for example, oral, rectal, intradermal, or subcutaneous implantation, or by implantation at the desired target site. Sustained-release formulations may contain the compound dispersed in a carrier matrix and / or contained within a reservoir surrounded by a rate controlling membrane. Excipients for use within such formulations are biocompatible, and may also be biodegradable; preferably the formulation provides a relatively constant level of active component release. The amount of pharmaceutical agent contained within a sustained release formulation depends upon the site of implantation, the rate and expected duration of release, and the nature of the condition, disease or disorder to be treated or prevented.

[0262] In certain embodiments, the pharmaceutical compositions comprising a pharmaceutical agent are formulated for transdermal, intradermal, or topical administration. The compositions can be administered using a syringe, bandage, transdermal patch, insert, or syringe-like applicator, as a powder / talc or other solid, liquid, spray, aerosol, ointment, foam, cream, gel, paste. This preferably is in the form of a controlled release formulation or sustained release formulation administered topically or injected directly into the skin adjacent to or within the area to be treated, e.g., intradermally or subcutaneously. The active compositions can also be delivered via iontophoresis Preservatives can be used to prevent the growth of fungi and othermicroorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and combinations thereof.

[0263] Pharmaceutical compositions comprising a pharmaceutical agent can be formulated as emulsions for topical application. An emulsion contains one liquid distributed in the body of a second liquid. The emulsion may be an oil-in-water emulsion or a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. The oil phase may contain other oily pharmaceutically approved excipients. Suitable surfactants include, but are not limited to, anionic surfactants, non-ionic surfactants, cationic surfactants, and amphoteric surfactants. Compositions for topical application may also include at least one suitable suspending agent, antioxidant, chelating agent, emollient, or humectant.

[0264] Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and / or gelling agents. Lotions may be formulated with an aqueous or oily base and will in general also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents, or coloring agents. Liquid sprays may be delivered from pressurized packs, for example, via a specially shaped closure. Oil-in- water emulsions can also be used in the compositions, patches, bandages and articles. These systems are semisolid emulsions, micro-emulsions, or foam emulsion systems.

[0265] In some embodiments, the pharmaceutical agent described herein can be formulated as in inhalant. Inhaled methods can deliver medication directly to the airway. The pharmaceutical agent can be formulated as aerosols, microspheres, liposomes, or nanoparticles. The pharmaceutical agent can be formulated with solvents, gases, nitrates, or any combinations thereof. Compositions described herein are optionally formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations are optionally nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory bronchioles. Liquid aerosol and inhalable dry powder formulations are preferably delivered throughout the endobronchial tree to the terminal bronchioles and eventually to the parenchymal tissue.

[0266] Aerosolized formulations described herein are optionally delivered using an aerosol forming device, such as a jet, vibrating porous plate or ultrasonic nebulizer, preferably selected to allow the formation of aerosol particles having with a mass medium average diameter predominantly between 1 to 5 ^. Further, the formulation preferably has balanced osmolarity ioniceffective dose of the pharmaceutical agent. Additionally, the aerosolized formulation preferably does not impair negatively the functionality of the airways and does not cause undesirable side effects.

[0267] Aerosolization devices suitable for administration of aerosol formulations described herein include, for example, jet, vibrating porous plate, ultrasonic nebulizers and energized dry powder inhalers, that are able to nebulize the formulation into aerosol particle size predominantly in the size range from 1-5 ^. Predominantly in this application means that at least 70% but preferably more than 90% of all generated aerosol particles are within 1-5 ^ range. A jet nebulizer works by air pressure to break a liquid solution into aerosol droplets. Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate. An ultrasonic nebulizer works by a piezoelectric crystal that shears a liquid into small aerosol droplets. A variety of suitable devices are available, including, for example, AeroNeb ^ ^ and AeroDose ^ ^ ^vibrating porous plate nebulizers (AeroGen, Inc., Sunnyvale, California), Sidestream ^ nebulizers (Medic-Aid Ltd., West Sussex, England), Pari LC ^ and Pari LC Star ^ jet nebulizers (Pari Respiratory Equipment, Inc., Richmond, Virginia), and Aerosonic ^ ^ (DeVilbiss Medizinische Produkte (Deutschland) GmbH, Heiden, Germany) and UltraAire ^ (Omron Healthcare, Inc., Vernon Hills, Illinois) ultrasonic nebulizers.

[0268] In some embodiments, the pharmaceutical agent(s) can be formulated with oleaginous bases or ointments to form a semisolid composition with a desired shape. In addition to the pharmaceutical agent, these semisolid compositions can contain dissolved and / or suspended bactericidal agents, preservatives and / or a buffer system. A petrolatum component that may be included may be any paraffin ranging in viscosity from mineral oil that incorporates isobutylene, colloidal silica, or stearate salts to paraffin waxes. Absorption bases can be used with an oleaginous system. Additives may include cholesterol, lanolin (lanolin derivatives, beeswax, fatty alcohols, wool wax alcohols, low HLB (hydrophobellipophobe balance) emulsifiers, and assorted ionic and nonionic surfactants, singularly or in combination.

[0269] Controlled or sustained release transdermal or topical formulations can be achieved by the addition of time-release additives, such as polymeric structures, matrices, that are available in the art. For example, the compositions may be administered through use of hot-melt extrusion articles, such as bioadhesive hot-melt extruded film. The formulation can comprise a cross-linked polycarboxylic acid polymer formulation. A cross-linking agent may be present in an amount that provides adequate adhesion to allow the system to remain attached to target epithelial or endot

[0270] An insert, transdermal patch, bandage or article can comprise a mixture or coating of polymers that provide release of the pharmaceutical agents at a constant rate over a prolonged period of time. In some embodiments, the article, transdermal patch or insert comprises water- soluble pore forming agents, such as polyethylene glycol (PEG) that can be mixed with water insoluble polymers to increase the durability of the insert and to prolong the release of the active ingredients.

[0271] Transdermal devices (inserts, patches, bandages) may also comprise a water insoluble polymer. Rate controlling polymers may be useful for administration to sites where pH change can be used to effect release. These rate controlling polymers can be applied using a continuous coating film during the process of spraying and drying with the active compound. In one embodiment, the coating formulation is used to coat pellets comprising the active ingredients that are compressed to form a solid, biodegradable insert.

[0272] A polymer formulation can also be utilized to provide controlled or sustained release. Bioadhesive polymers described in the art may be used. By way of example, a sustained-release gel and the compound may be incorporated in a polymeric matrix, such as a hydrophobic polymer matrix. Examples of a polymeric matrix include a microparticle. The microparticles can be microspheres, and the core may be of a different material than the polymeric shell. Alternatively, the polymer may be cast as a thin slab or film, a powder produced by grinding or other standard techniques, or a gel such as a hydrogel. The polymer can also be in the form of a coating or part of a bandage, stent, catheter, vascular graft, or other device to facilitate delivery of the pharmaceutical agent. The matrices can be formed by solvent evaporation, spray drying, solvent extraction and other methods known to those skilled in the art.

[0273] Kits with unit doses of one or more of the agents described herein, usually in oral or injectable doses, are provided. Such kits may include a container containing the unit dose, an informational package insert describing the use and attendant benefits of the drugs in treating disease, and optionally an appliance or device for delivery of the composition. Methods of Treatment

[0274] In an aspect, the present disclosure provides compounds that inhibit KRas G12 mutants. In some cases, the method may inhibit KRas G12 mutants activity in a cell. In some cases, inhibitng KRas G12 mutants activity in a cell may include contacting the cell in which inhibition of KRas G12 mutants activity is desired with an effective amount of a compound of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), or pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition. In some cases, the pharmaceutical compin vitro. In some cases, the contacting is in vivo. As used herein, the term "contacting" refers to the bringing together of indicated moieties in an in vitro system or an in vivo system. For example, "contacting" a KRas G12D and / or other G12 mutants with a compound provided herein includes the administration of a compound provided herein to an individual or patient, such as a human, having KRas G12D and / or other G12 mutants, as well as, for example, introducing a compound provided herein into a sample containing a cellular or purified preparation containing the KRas G12D and / or other G12 mutants. In some cases, a cell in which inhibition of KRas G12D and / or other G12 mutants activity is desired is contacted with an effective amount of a compound or salt of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB),or a pharmaceutical composition of any one thereof to negatively modulate the activity of KRas G12D and / or other G12 mutants. In some cases, by negatively modulating the activity of KRas G12D and / or other G12 mutants, the methods described herein are designed to inhibit undesired cellular proliferation resulting from enhanced KRas G12D and / or other G12 mutants activity within the cell. The cells may be contacted in a single dose or multiple doses in accordance with a particular treatment regimen to effect the desired negative modulation of KRas G12D and / or other G12 mutants. The ability of compounds to bind KRas G12D and / or other G12 mutants may be monitored in vitro using well known methods.

[0275] In some embodiments, the inhibitory activity of exemplary compounds in cells may be monitored, for example, by measuring the inhibition of KRas G12D and / or other G12 mutants activity of the amount of phosphorylated ERK.

[0276] In another aspect, methods of treating cancer in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt of any one thereof and a pharmaceutically acceptable excipient are provided. The compositions and methods provided herein may be used for the treatment of a KRas G12D and / or other G12 mutants-associated cancer in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the compound or pharmaceutically acceptable salt thereof are provided. In some cases, the KRas G12D and / or other G12 mutants associated cancer is lung cancer. The compositions and methods provided herein may be used for the treatment of a wide variety of cancers including tumors such as lung, prostate, breast, brain, skin, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compastrocytic, breast, cervical, colorectal, endometrial, esophageal, gastric, head and neck, hepatocellular, laryngeal, lung, oral, ovarian, prostate and thyroid carcinomas and sarcomas. More specifically, these compounds, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, can be used to treat: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic) acute lymphoblastic leukemiachronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma. In some cases, the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer. In some cases, the cancer is non-small cell lung cancer. In some cases, the cancer is a solid tumor cancer. In some cases, the concentration and route of administration to the patient will vary depending on the cancer to be treated. The compounds, pharmaceutically acceptable salts thereof and pharmaceutical compositions comprising such compounds and salts also may be co-administered with other anti-neoplastic compounds, e.g., chemotherapy, or used in combination with other treatments, such as radiation or surgical intervention, either as an adjuvant prior to surgery or post-operatively.

[0277] Also provided herein is a compound of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in therapy.

[0278] Also provided herein is a compound of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in the treatment of cancer.

[0279] Also provided herein is a compound of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in the inhibition of KRas G12D and / or other G12 mutants.

[0280] Also provided herein is a compound of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, for use in the treatment of a KRas G12D and / or other G12 mutants associated disease or disorder.

[0281] Also provided herein is the use of a compound of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cancer.

[0282] Also provided herein is a use of a compound of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, in the manufacture of a medicament for the inhibition of activity of KRas G12D and / or other G12 mutants.

[0283] Also provided herein is the use of a compound of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), or a pharmaceutically acceptable salt of any one thereof, or a pharmaceutical composition of any one thereof, in the manufacture of a medicament for the treatment of a KRas G12D and / or other G12 mutants-associated disease or disorder.

[0284] In another aspect, the present disclosure provides a method for treating cancer in a patient in need thereof, the method comprising (a) determining that cancer is associated with a KRas G12D mutation and / or other G12 mutants (e.g., a KRas G12D and / or other G12 mutants- associated cancer) (e.g., as determined using a regulatory agency-approved, e.g., FDA- approved, assay or kit); and (b) administering to the patient a therapeutically effective amount of a compound of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0285] The compounds described herein can be used in the preparation of medicaments for the prevention or treatment of diseases or conditions. In addition, a method for treating any of the diseases or conditions described herein in a subject in need of such treatment, involves administration of pharmaceutical compositions containing at least one compound described herein, or a pharmaceutically acceptable salt, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, in therapeutically effective amounts to said subject.

[0286] The compositions containing the compound(s) described herein can be administered for prophylactic and / or therapeutic treatments. In therapeutic applications, the compositions are administered to a patient already suffering from a disease or condition, in an amount sufficient to cure or at least partially arrest the symptoms of the disease or condition. Amounts effective for this use will depend on the severity and course of the disease or condition, previous therapy, the patient's health status, weight, and response to the drugs, and the judgment of the treating physician.

[0287] In prophylactic applications, compositions containing the compounds described herein are administered to a patient susceptible to or otherwise at risk of a particular disease, disorder or condition. Such an amount is defined to be a "prophylactically effective amount or dose." In this use, the precise amounts also depend on the patient's state of health, weight, and the like. When used in a patient, effective amounts for this use will depend on the severity and course of the disease, disorder or condition, previous therapy, the patient's health status and response to the drugs, and the judgment of the treating physician.

[0288] In the case wherein the patient’s condition does not improve, upon the doctor’s discretion the administration of the compounds may be administered chronically, that is, for anextended period of time, including throughout the duration of the patient’s life in order to ameliorate or otherwise control or limit the symptoms of the patient’s disease or condition.

[0289] Once improvement of the patient's conditions has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[0290] The amount of a given agent that will correspond to such an amount will vary depending upon factors such as the particular compound, disease or condition and its severity, the identity (e.g., weight) of the subject or host in need of treatment, but can nevertheless be determined in a manner recognized in the field according to the particular circumstances surrounding the case, including, e.g., the specific agent being administered, the route of administration, the condition being treated, and the subject or host being treated. In general, however, doses employed for adult human treatment will typically be in the range of about 0.02 - about 5000 mg per day, in some embodiments, about 1 – about 1500 mg per day. The desired dose may conveniently be presented in a single dose or as divided doses administered simultaneously (or over a short period of time) or at appropriate intervals, for example as two, three, four or more sub-doses per day.

[0291] The pharmaceutical composition described herein may be in unit dosage forms suitable for single administration of precise dosages. In unit dosage form, the formulation is divided into unit doses containing appropriate quantities of one or more compound. The unit dosage may be in the form of a package containing discrete quantities of the formulation. Non-limiting examples are packaged tablets or capsules, and powders in vials or ampoules. Aqueous suspension compositions can be packaged in single-dose non-reclosable containers. Alternatively, multiple- dose reclosable containers can be used, in which case it is typical to include a preservative in the composition. By way of example only, formulations for parenteral injection may be presented in unit dosage form, which include, but are not limited to ampoules, or in multi-dose containers, with an added preservative.

[0292] Toxicity and therapeutic efficacy of such therapeutic regimens can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, including, but not limited to, the determination of the LD50(the dose lethal to 50% of the population) and the ED50(the dose therapeutically effective in 50% of the population). The dose ratio between the toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio between LD50 and Ecell culture assays and animal studies can be used in formulating a range of dosage for use in human. The dosage of such compounds lies preferably within a range of circulating concentrations that include the ED50 with minimal toxicity. The dosage may vary within this range depending upon the dosage form employed and the route of administration utilized.

[0293] In certain embodiments, the invention provides a method of treating or preventing a disease, state or condition in a patient in need thereof comprising administering to the patient an effective amount of a compound of any one of embodiments of the invention or a pharmaceutically acceptable salt thereof. The disease, state or condition may be selected from a group as described elsewhere herein. Bifunctional Compounds

[0294] In some embodiments, compounds herein can adopt to selectively eliminate an over activated KRas signaling which is induced by KRas mutations by directly binding with the mutated KRas protein, either by stabilizing its GDP bound form (the inactive form) or by blocking the interaction between GTP bound form and its downstream target protein. In some embodiments, another way is to hijack the protein degradation mechanism in a cell and leverage E3 ligases’ (like VHL, CRBN or IAPs) substrate specificity through a bi-functional molecule called Proteolysis targeting chimera (PROTAC) (Winter GE, Buckley DL, Paulk J, Roberts JM, Souza A, Dhe-Paganon S, Bradner JE. DRUG DEVELOPMENT. Phthalimide conjugation as a strategy for in vivo target protein degradation. Science.2015 Jun 19; 348 (6241): 1376-81), which can bind with both mutated KRas protein and E3 ligase, create interactions between those two proteins and induce KRas degradation.

[0295] Disclosed herein is a bifunctional compound composed of a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety, which may induce proteasome-mediated degradation of selected proteins. In some embodiments, the bifunctional compound comprises a target protein (i.e., KRAS G12D)-binding moiety and an E3 ubiquitin ligase-binding moiety known in the art. In some embodiments, disclosed herein is the use of the compound disclosed herein in the preparation of degrading a target protein compound by using chemical modification of the compound disclosed herein. In some cases, the target protein- binding moiety is derived from a compound of Formula (I), Formula (I-A), Formula (I-AA), or Formula (I-BB). Preparation of Compounds

[0296] The compounds of the present disclosure can generally be prepared in a number of waysof the present disclosure can be synthesized using the methods described herein, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art.

[0297] The compounds of the present disclosure may be prepared as described in the schemes and examples described elsewhere herein. EXAMPLES

[0298] The following examples further illustrate the invention but, of course, should not be construed as in any way limiting its scope.

[0299] The following synthetic schemes are provided for purposes of illustration, not limitation. The following examples illustrate the various methods of making compounds described herein. It is understood that one skilled in the art may be able to make these compounds by similar methods or by combining other methods known to one skilled in the art. It is also understood that one skilled in the art would be able to make, in a similar manner as described below by using the appropriate starting materials and modifying the synthetic route as needed. In general, starting materials and reagents can be obtained from commercial vendors or synthesized according to sources known to those skilled in the art or prepared as described herein.

[0300] The present disclosure provides processes for preparing compounds the compounds described herein (described in greater detail below).

[0301] Certain compounds of Tables herein can be prepared employing appropriate reagents in the schemes described herein.

[0302] Intermediate 1. Preparation of 2-aminospiro[5,6-dihydrocyclopenta[b]thiophene-4,3'- azetidine]-3-carbonitrile (Int-1).

[0303] Step 1. Synthesis of tert-butyl 2-amino-3-cyano-spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-1'-carboxylate (Int-1a). A solution of propanedinitrile (219.93 mg, 3.33 mmol) and tert-butyl 5-oxo-2-azaspiro[3.4]octane-2- carboxylate (500 mg, 2.22 mmol) in DMF (5 mL) was added L-proline (255 mg, 2.22 mmol) and sulfur (113.5 mg, 3.33 mmol) at 25 °C under N2. The reaction was stirred at 60 °C for 4 h. The mixtuH2O from 5.0% to 95%) to afford tert-butyl 2-amino-3-cyano-spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-1'-carboxylate (Int-1a, 380 mg, 1.244 mmol, 56.1% yield) as yellow solid. LCMS calculated for C15H20N3O2S (M+H)+m / z = 306.1, found: 306.1.1H NMR (400 MHz, CD3OD) δ 4.19 (s, 2H), 3.95 (d, J = 8.1 Hz, 2H), 2.76 – 2.69 (m, 2H), 2.69 – 2.61 (m, 2H), 1.45 (s, 9H).

[0304] Step 2. Synthesis of 2-aminospiro[5,6-dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3- carbonitrile (Int-1). A solution of tert-butyl 2-amino-3-cyano-spiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-1'-carboxylate (Int-1a, 380 mg, 1.24 mmol) in DCM (5 mL) was added TFA (1.91 mL, 24.89 mmol) at 25 °C under N2. Then the reaction was stirred at 20 °C for 1 h. The mixture was concentrated and the crude product 2-aminospiro[5,6- dihydrocyclopenta[b]thiophene-4,3'-azetidine]-3-carbonitrile;2,2,2-trifluoroacetic acid (Int-1, 380 mg, 0.678 mmol, 54.5% yield) was used directly for the next step. LCMS calculated for C10H12N3S (M+H)+m / z = 206.1, found: 206.1.

[0305] Intermediate 2. Synthesis of 2-aminospiro[6H-thieno[2,3-c]thiophene-4,3'-azetidine]- 3-carbonitrile; methanesulfonic acid

[0306] Step 1. Preparation of O1-tert-butyl O3-methyl 3-bromoazetidine-1,3-dicarboxylate (Int-2a). To a solution of [bis(trimethylsilyl)amino]lithium (2798.55 mg, 16.72 mmol) in THF (60mL) was added dropwise O1-tert-butyl O3-methyl azetidine-1,3-dicarboxylate (3 g, 13.94 mmol) in THF (30mL) at -70 °C under N2. Then the mixture was stirred at RT for 15 min, and carbon tetrabromide (6933.03 mg, 20.91 mmol) in THF (30 mL) was added dropwise. The resulting mixture was stirred at RT for 16 h. The reaction mixture was quenched with NH4Cl aqueous, and wash with NaHCO3aqueous, brine, concentrated, purified by flash column chromatography (0% - 25% EtOAc / PE) to afford O1-tert-butyl O3-methyl 3-bromoazetidine-1,3- dicarboxylate (Int-2a, 2.30 g, 7.82 mmol, 56.10 %yield) as a yellow oil. LCMS calculated for C10H17BrNO4(M+H)+m / z = 295.0; found: 239.8 (M-tBu).1H NMR (400 MHz, CDCl3) δ = 4.65 (dd, J=10.3, 1.3 Hz, 2H), 4.30 (dd, J=10.3, 1.3 Hz, 2H), 3.85 (s, 3H), 1.45 (s, 9H).

[0307] Step 2. Preparation of O1-tert-butyl O3-methyl 3-(3-methoxy-3-oxo- propyl)sulfanylazetidine-1,3-dicarboxylate (Int-2b). To a solution of O1-tert-butyl O3-methyl 3- bromoazetidine-1,3-dicarboxylate (Int-2a,1.5g, 5.1mmol) in DMF (16 mL) was added methyl 3- sulfanylpropanoate (1348.2 mg, 11.22 mmol) and K2CO3(2819.27 mg, 20.4 mmol) at 20 °C under N2. The mixture was stirred at RT overnight. The reaction mixture was quenched with water, extracted with EtOAc, washed with water and brine, concentrated, purified by flash column chromatography (0% - 25% EtOAc in PE) to afford O1-tert-butyl O3-methyl 3-(3- methoxy-3-oxo-propyl)sulfanylazetidine-1,3-dicarboxylate (Int-2b, 1.60 g, 4.80 mmol, 94.11% yield) as a colorless oil. LCMS calculated for C14H24NO6S (M+H)+m / z = 334.13; found: 233.9 (M-Boc).

[0308] Step 3. Preparation of O2-tert-butyl O7-methyl 8-oxo-5-thia-2-azaspiro[3.4]octane-2,7- dicarboxylate (Int-2c). To a solution of O1-tert-butyl O3-methyl 3-(3-methoxy-3-oxo- propyl)sulfanylazetidine-1,3-dicarboxylate (Int-2b, 200 mg, 3.6 mmol) in THF (20 mL) was added t-BuONa (691.78 mg, 7.2 mmol) in five batches at 0 °C under N2. Then the mixture was stirred at 0 °C for 2 h. The reaction was quenched with water and the pH was adjusted to 5-6 by acetic acid. The reaction mixture was extracted with EtOAc, washed with brine and dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography (10% - 30% EtOAc / PE) to afford O2-tert-butyl O7-methyl 8-oxo-5-thia-2-azaspiro[3.4]octane-2,7-dicarboxylate (Int-2c, 800 mg, 2.65 mmol, 73.75 %yield) as light red oil. LCMS calculated for C13H20NO5S (M+H)+m / z = 302.36; found: 246.1(M-tBu).1H NMR (400 MHz, CDCl3) δ = 11.02 (s, 1H), 4.47 (d, J=9.9 Hz, 2H), 4.03 (d, J=9.8 Hz, 2H), 3.82 (s, 3H), 3.72 (s, 2H), 1.45 (s, 9H).

[0309] Step 4. Preparation of tert-butyl 8-oxo-5-thia-2-azaspiro[3.4]octane-2-carboxylate (Int-2d). To a solution of O2-tert-butyl O7-methyl 8-oxo-5-thia-2-azaspiro[3.4]octane-2,7- dicarboxylate (Int-2c, 800 mg, 2.65 mmol) in DMSO (12 mL) was added LiCl (225.06 mg, 5.31 mmol) and water (1.2 mL) at rt under N2. The mixture was heated at 160 °C for 1.5 h, The reaction mixture was quenched with water, extracted with EtOAc, washed with brine. The mixture was dried over Na2SO4and concentrated. The residue was purified by flash column chromatography (0% - 30% EtOAc in PE) to afford tert-butyl 8-oxo-5-thia-2- azaspiro[3.4]octane-2-carboxylate (Int-2d, 480 mg, 1.97 mmol, 74.31 %yield) as a colorless oil. LCMS calculated for C11H18NO3S(M+H)+m / z = 244.32; found: 187.9 (M-tBu).1H NMR (400 MHz, CDCl3) δ = 4.27 (d, J=9.1 Hz, 2H), 3.93 (d, J=9.3 Hz, 2H), 2.97 (t, J=7.1 Hz, 2H), 2.70 (t, J=7.1 Hz, 2H), 1.44 (s, 9H).

[0310] Step 5. Preparation of tert-butyl 2-amino-3-cyano-spiro[6H-thieno[2,3-c]thiophene-4,3'- azetidine]-1'-carboxylate (Int-2e) Propanedinitrile (19548 mg 296 mmol) was added to asolution of tert-butyl 8-oxo-5-thia-2-azaspiro[3.4]octane-2-carboxylate (480 mg, 1.97 mmol), Sulfur (94.93 mg, 2.96 mmol) and ammonium acetate (228.08 mg, 2.96 mmol) in Ethanol (7 mL) at RT. The mixture was heated at 60 °C for 1.5 h. The reaction was quenched with water and was extracted with EtOAc. The combined extracts were dried, filtered, and concentrated. The residue was purified by chromatography (20-30% EtOAc in PE) to afford tert-butyl 2-amino-3-cyano- spiro[6H-thieno[2,3-c]thiophene-4,3'-azetidine]-1'-carboxylate ((Int-2e, 610mg, 1.88 mmol, 95.60 %yield) as yellow solid. LCMS calculated for C14H18N3O2S2(M+H)+m / z =324.08; found: 268.0 (M-tBu), 224.0 (M-Boc).

[0311] Step 6. Preparation of 2-aminospiro[6H-thieno[2,3-c]thiophene-4,3'-azetidine]-3- carbonitrile;methanesulfonic acid (Int-2). A solution of tert-butyl 2-amino-3-cyano-spiro[6H- thieno[2,3-c]thiophene-4,3'-azetidine]-1'-carboxylate (Int-2e, 250 mg, 0.77 mmol) in IPA (2.5 mL) was added methanesulfonic acid (0.1 mL, 1.54 mmol) at RT. The mixture was heated at 60 °C for 8 h. The reaction was cooled down and filtered. The solid was wash with IPA and dried to afford 2-aminospiro[6H-thieno[2,3-c]thiophene-4,3'-azetidine]-3-carbonitrile;methanesulfonic acid (Int-2, 210 mg, 0.657 mmol, 85.00 %yield) as grey solid. LCMS calculated for C9H10N3S2 (M+H)+m / z =224.31; found: 224.2.

[0312] Example 1. Exemplary synthesis of 2-amino-1'-[(11S)-4-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9,13-dioxa-1,3,5- triazatricyclo[9.5.0.02,7]hexadeca-2,4,6-trien-6-yl]spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'- azetidine]-3-carbonitrile (Compound 1)

[0313] Step 1. Synthesis of (R)-4-chloro-6-(3-(hydroxymethyl)-1,4-oxazepan-4-yl)-2- (methylthio)pyrimidine-5-carbaldehyde (1a). The mixture of 4,6-dichloro-2-methylsulfanyl- pyrimidine-5-carbaldehyde (50 mg, 0.22 mmol), K2CO3 (92.79 mg, 0.67 mmol) and [(3R)-1,4- oxazemL) was stirred at r.t for 4 h under N2. The reaction mixture was concentrated in vacuo and the residue was purified using FCC (EtOAc in PE 0 to 20%) to give the product 4-chloro-6-[(3R)-3- (hydroxymethyl)-1,4-oxazepan-4-yl]-2-methylsulfanyl-pyrimidine-5-carbaldehyde (1a, 50 mg, 0.157 mmol, 70 % yield) as a light-yellow solid. LCMS calculated for C12H17ClN3O3S (M+H)+m / z =318.1; found: 318.1.

[0314] Step 2. Synthesis of (R)-(4-(6-chloro-5-(hydroxymethyl)-2-(methylthio)pyrimidin-4- yl)-1,4-oxazepan-3-yl)methanol (1b). To the solution of 4-chloro-6-[(3R)-3-(hydroxymethyl)-1,4- oxazepan-4-yl]-2-methylsulfanyl-pyrimidine-5-carbaldehyde (1a, 140 mg, 0.44 mmol) in MeOH (3 mL) was added NaBH4 (48.9 mg, 1.32 mmol) at RT under N2. The resulting mixture was stirred at RT for 3 h. The reaction was quenched with aq. NaHCO3and extracted with DCM (30 mLx3). The combined extracts were washed with water followed by brine, dried over Na2SO4and concentrated in vacuo. The residue was purified using FCC (silica gel, eluting EtOAc in PE 0% to 50%) to afford the title product [4-chloro-6-[(3R)-3-(hydroxymethyl)-1,4-oxazepan-4-yl]-2- methylsulfanyl-pyrimidin-5-yl]methanol (1b, 90 mg, 0.281 mmol, 63.88 %yield) as a yellow solid. LCMS calculated for C12H19ClN3O3S (M+H)+m / z =320.1; found: 320.1.

[0315] Step 3. Synthesis of (S)-4-chloro-2-(methylthio)-7a,8,11,12-tetrahydro-5H,7H,10H- [1,4]oxazepino[3,4-c]pyrimido[4,5-e][1,4]oxazepine (1c). The mixture of [4-chloro-6-[(3R)-3- (hydroxymethyl)-1,4-oxazepan-4-yl]-2-methylsulfanyl-pyrimidin-5-yl]methanol (1b, 90 mg, 0.28 mmol) and TsOH (145.38 mg, 0.84 mmol) in Toluene (3 mL) was heated at 110 ℃ under N2 for overnight. The reaction was cooled to r.t and the solvent was removed in vacuo. The residue was diluted with H2O, then basified to pH 7-8 with sat. NaHCO3and extracted with DCM (3 x 20 mL). The combined extracts were washed with brine, dried (Na2SO4) and concentrated under reduced pressure to give the crude product. The crude product was purified by FCC (EtOAc in PE 0 to 30%) to give the product (11S)-6-chloro-4-methylsulfanyl-9,13-dioxa-1,3,5- triazatricyclo[9.5.0.02,7]hexadeca-2,4,6-triene (1c, 56 mg, 0.186 mmol, 65.94 % yield) as a yellow solid. LCMS calculated for C12H17ClN3O2S (M+H)+m / z =302.07; found: 302.1.

[0316] Step 4. Synthesis of (S)-4-chloro-2-(methylsulfonyl)-7a,8,11,12-tetrahydro- 5H,7H,10H-[1,4]oxazepino[3,4-c]pyrimido[4,5-e][1,4]oxazepane (1d). To the solution of (11S)- 6-chloro-4-methylsulfanyl-9,13-dioxa-1,3,5-triazatricyclo[9.5.0.02,7]hexadeca-2,4,6-triene (1c, 50 mg, 0.17 mmol) in THF (6 mL) and Water (3 mL) was added Oxone (509.26 mg, 0.83 mmol). The reaction was stirred at room temperature for 4h. The mixture was quenched with H2O and was extracted with DCM (15 mLx3). The combined extracts were washed with water and brine. The organic phase was dried (Na2SO4) and concentrated in vacuo to give the crude product (11S)-6-chloro-4-methylsulfonyl-913-dioxa-135-triazatricyclo[950027]hexadeca-246-triene(1d, 51 mg, 92%) as a yellow solid. The crude product was used in the next step directly without further purification. LCMS calculated for C12H17ClN3O4S (M+H)+m / z =334.06; found: 334.1.

[0317] Step 5. Synthesis of (S)-4-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7a,8,11,12-tetrahydro-5H,7H,10H-[1,4]oxazepino[3,4-c]pyrimido[4,5- e][1,4]oxazepine (1e). To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methanol (26.23 mg, 0.16 mmol) in DMSO (2 mL) was added Sodium tert-butoxide (14.4 mg, 0.15 mmol) at r.t under N2. The reaction was stirred for 1 h, followed by the addition of (11S)-6- chloro-4-methylsulfonyl-9,13-dioxa-1,3,5-triazatricyclo[9.5.0.02,7]hexadeca-2,4,6-triene (1d, 50 mg, 0.15 mmol). The reaction was stirred at rt for 2 h and was quenched by H2O (10 mL) followed by the extraction of Et2O (3 x 15 mL). The combined extracts were washed with brine, dried (Na2SO4), and concentrated under reduced pressure to give the crude product. It was purified using FCC (MeOH in DCM 0 to 10%, v / v)) to afford the title product (11S)-6-chloro-4-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9,13-dioxa-1,3,5- triazatricyclo[9.5.0.02,7]hexadeca-2,4,6-triene (1e, 40 mg, 0.0969 mmol, 64.67 % yield) as a white solid. LCMS calculated for C19H26ClFN4O3 (M+H)+m / z =412.17; found: 413.2.

[0318] Step 6. Synthesis of 2'-amino-1-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-7a,8,11,12-tetrahydro-5H,7H,10H-[1,4]oxazepino[3,4-c]pyrimido[4,5- e][1,4]oxazepin-4-yl)-5',6'-dihydrospiro[azetidine-3,4'-cyclopenta[b]thiophene]-3'-carbonitrile (Compound 1). The mixture of (11S)-6-chloro-4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-9,13-dioxa-1,3,5-triazatricyclo[9.5.0.02,7]hexadeca-2,4,6- triene (1e, 25 mg, 0.06 mmol) and 2-aminospiro[5,6-dihydrocyclopenta[b]thiophene-4,3'- azetidine]-3-carbonitrile (124.29 mg, 0.61 mmol) in TEA (0.5 mL, 3.6 mmol) was heated at 110 ℃ under N2 in a sealed tube for 1 hour. The reaction was cooled to r.t and then purified using prep-TLC (silica gel, eluent with DCM / MeOH = 10 / 1, v / v) followed by reverse phase FCC (C18, Eluting with MeCN in aqueous 0.1% NH4HCO3) to give the title product 2-amino-1'-[(11S)-4- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9,13-dioxa-1,3,5- triazatricyclo[9.5.0.02,7]hexadeca-2,4,6-trien-6-yl]spiro[5,6-dihydrocyclopenta[b]thiophene-4,3'- azetidine]-3-carbonitrile (Compound 1, 6.3 mg, 0.0106 mmol, 17.56 % yield) as a light yellow solid. LCMS calculated for C29H37FN7O3S (M+H)+m / z = 582.71; found: 583.2.1H NMR (400 MHz, CD3OD) δ 5.35 – 5.16 (m, 1H), 4.49 (d, J = 14.0 Hz, 1H), 4.39 (dd, J = 11.2, 5.8 Hz, 2H), 4.27 – 4.11 (m, 4H), 4.02 (dd, J = 13.3, 9.5 Hz, 2H), 3.95 – 3.72 (m, 7H), 3.64 (m, 1H), 3.24 – 3.15 (m, 2H), 3.13 (s, 1H), 2.96 (td, J = 9.2, 5.7 Hz, 1H), 2.79 – 2.66 (m, 4H), 2.34 – 2.06 (m, 3H), 2.04 – 1.77 (m, 5H).

[0319] Example 2. Exemplary synthesis of 2-amino-1'-[(11R)-4-[[1- (morpholinomethyl)cyclopropyl]methoxy]-8-oxo-9-oxa-1,3,5,13- tetrazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-trien-6-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'- azetidine]-3-carbonitrile (Compound 2) Boc N (R) Boc Boc N N N O M N

[003] ep . yn es s o me y -[( )- - er - u oxycar onyl-2- (hydroxymethyl)piperazin-1-yl]-6-chloro-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]pyrimidine-5-carboxylate (2a). A solution of methyl 4,6-dichloro-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]pyrimidine-5-carboxylate (300.00 mg, 0.72 mmol), tert-butyl (3R)-3-(hydroxymethyl)piperazine-1-carboxylate (186.26 mg, 0.86 mmol) and DIEA (0.38 mL, 2.15 mmol) in DCM (5 mL) was stirred at room temperature under N2for 6 h. The reaction was quenched with aqueous NH4Cl solution, and then extracted with EtOAc (20 mLx3). The combined extracts were washed with water, brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC (silica gel, eluting with MeOH in DCM 0% to 5%, v / v) to afford methyl 4-[(2R)-4-tert-butoxycarbonyl-2-(hydroxymethyl)piperazin-1-yl]- 6-chloro-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]pyrimidine-5-carboxylate (2a, 311.00 mg, 0.56 mmol, 77.93% yield) as a white solid. LCMS calculated for C25H39ClN5O7(M+H)+m / z =556.26; found: 556.3.

[0321] Step 2: tert-butyl (11R)-6-chloro-4-[[1-(morpholinomethyl)cyclopropyl]methoxy]-8- oxo-9-oxa-1,3,5,13-tetrazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-triene-13-carboxylate (2b)

[0322] To the solution of methyl 4-[(2R)-4-tert-butoxycarbonyl-2-(hydroxymethyl)piperazin- 1-yl]-6-chloro-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]pyrimidine-5-carboxylate (2a, 275.00 mg 049 mmol) in THF (25 mL) was added sodium tert-butoxide (4753 mg 049 mmol)at 0 ℃ under N2. The mixture was allowed to warm to r.t and stirred for 16h. The reaction was quenched with NH4Cl aqueous solution and extracted with EtOAc (20 mLx3). The combined extracts were washed with water and brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by FCC (MeOH in DCM 0% to 5%, v / v) to afford tert-butyl (11R)-6-chloro-4-[[1- (morpholinomethyl)cyclopropyl]methoxy]-8-oxo-9-oxa-1,3,5,13- tetrazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-triene-13-carboxylate (2b, 75.00 mg, 0.14 mmol, 28.94% yield) as a white solid. LCMS calculated for C24H35ClN5O6(M+H)+m / z = 524.23; found: 524.6.

[0323] Step 3: tert-butyl (11R)-6-(2-amino-3-cyano-spiro[6H-thieno[3,4-b]thiophene-4,3'- azetidine]-1'-yl)-4-[[1-(morpholinomethyl)cyclopropyl]methoxy]-8-oxo-9-oxa-1,3,5,13- tetrazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-triene-13-carboxylate (2c). A solution of 2- aminospiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile;methanesulfonic acid (Int-2, 57.60 mg, 0.18 mmol), tert-butyl (11R)-6-chloro-4-[[1- (morpholinomethyl)cyclopropyl]methoxy]-8-oxo-9-oxa-1,3,5,13- tetrazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-triene-13-carboxylate (2b, 90.00 mg, 0.17 mmol) and DIEA (0.09 mL, 0.52 mmol) in DMSO (1 mL) was stirred at r.t under N2 overnight. The reaction was quenched with NH4Cl aqueous solution and extracted with EtOAc (20 mLx3). The combined extracts were washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by FCC (MeOH in DCM 0% to 8%) to afford tert-butyl (11R)-6-(2- amino-3-cyano-spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-1'-yl)-4-[[1- (morpholinomethyl)cyclopropyl]methoxy]-8-oxo-9-oxa-1,3,5,13- tetrazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-triene-13-carboxylate (2c, 91.00 mg, 0.13 mmol, 74.53% yield) as a white solid. LCMS calculated for C33H43N8O6S2 (M+H)+m / z = 711.28; found: 711.6.

[0324] Step 4: 2-amino-1'-[(11R)-4-[[1-(morpholinomethyl)cyclopropyl]methoxy]-8-oxo-9- oxa-1,3,5,13-tetrazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-trien-6-yl]spiro[6H-thieno[3,4- b]thiophene-4,3'-azetidine]-3-carbonitrile (Compound 2). To the solution of tert-butyl (11R)-6- (2-amino-3-cyano-spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-1'-yl)-4-[[1- (morpholinomethyl)cyclopropyl]methoxy]-8-oxo-9-oxa-1,3,5,13- tetrazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-triene-13-carboxylate (2c, 91.00 mg, 0.13 mmol) in DCM (1 mL) was added TFA (0.5 mL, 6.49 mmol). The mixture was stirred at r. t. for 2 h. The solvent was removed and the residue was purified by prep-HPLC (C18, MeCN in aqueous 0.1% NH4HCO3) to afford 2-amino-1'-[(11R)-4-[[1-(morpholinomethyl)cyclopropyl]methoxy]-8-oxo- 9-oxa-1,3,5,13-tetrazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-trien-6-yl]spiro[6H-thieno[3,4- b]thioa brown solid. LCMS calculated for C28H35N8O4S2(M+H)+m / z =611.22; found: 611.2.1H NMR (400 MHz, CD3OD) δ 4.90 – 4.97 (m, 1H), 4.71 – 4.82 (m, 1H), 4.52 – 4.68 (m, 1H), 3.80 – 4.48 (m, 9H), 3.66 (t, J = 4.8 Hz, 4H), 2.71 – 3.23 (m, 5H), 2.42 – 2.55 (m, 4H), 2.38 (d, J = 4.4 Hz, 2H), 0.65 (t, J = 5.2 Hz, 2H), 0.44 (t, J = 4.8 Hz, 2H).

[0325] Compound 3. 2-amino-1'-[(11S)-4-[[1-(morpholinomethyl)cyclopropyl]methoxy]-8- oxo-9-oxa-1,3,5,13-tetrazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-trien-6-yl]spiro[6H-thieno[3,4- b]thiophene-4,3'-azetidine]-3-carbonitrile [4S2( 6 (t, J (m, 2 [ xo- 5 a

[0328] Step 1. Synthesis of O1-tert-butyl O3-methyl (3R)-4-(6-chloro-2-methylsulfanyl-5- nitro-pyrimidin-4-yl)piperazine-1,3-dicarboxylate (4a). To the solution of 4,6-dichloro-2- methylsulfanyl-5-nitro-pyrimidine (294.81 mg, 1.23 mmol) in DCM (5 mL) were added O1-tert- butyl O3-methyl (3R)-piperazine-1,3-dicarboxylate (300.00 mg, 1.23 mmol) followed by DIEA (0.64 mL, 3.68 mmol) dropwise at -70 ℃ under N2. The mixture was stirred at -70 ℃ for 2 h. The reaction was quenched with aq. NH4Cl and extracted with EtOAc (20 mLx3). The combined extracts were washed with water and brine, dried (Na2SO4), and concentrated. The residue was purified by FCC (EtOAc in PE 0% to 30%, v / v) to afford O1-tert-butyl O3-methyl (3R)-4-(6- chloro-2-methylsulfanyl-5-nitro-pyrimidin-4-yl)piperazine-1,3-dicarboxylate (4a, 450.00 mg, 1.00 mmol, 81.81% yield) as a light yellow solid. LCMS calculated for C16H23ClN5O6S (M+H)+m / z = 448.11; found: 448.4.

[0329] Step 2. Synthesis of O1-tert-butyl O3-methyl (3R)-4-(6-chloro-2-methylsulfonyl-5- nitro-pyrimidin-4-yl)piperazine-1,3-dicarboxylate (4b). To the solution of O1-tert-butyl O3- methyl (3R)-4-(6-chloro-2-methylsulfanyl-5-nitro-pyrimidin-4-yl)piperazine-1,3-dicarboxylate (4a, 450.00 mg, 1.00 mmol) in THF (8 mL) and Water (8 mL) was added Oxone (2470.62 mg, 4.02 mmol). The reaction was stirred at room temperature for 3 h under N2. The mixture was quenched with aqueous NH4Cl solution and extracted with EtOAc (20 mLx3). The combined extracts were washed with water and brine, dried (Na2SO4), and concentrated in vacuo to give the crude O1-tert-butyl O3-methyl (3R)-4-(6-chloro-2-methylsulfonyl-5-nitro-pyrimidin-4- yl)piperazine-1,3-dicarboxylate (4b, 480.00 mg, 1.00 mmol, 99.55% yield) as a light-yellow oil. LCMS calculated for C16H23ClN5O8S (M+H)+m / z = 480.10; found: 424.3, 497.4.

[0330] Step 3. Synthesis of O1-tert-butyl O3-methyl (3R)-4-[6-(2-amino-3-cyano-spiro[6H- thieno[3,4-b]thiophene-4,3'-azetidine]-1'-yl)-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]-5- nitro-pyrimidin-4-yl]piperazine-1,3-dicarboxylate (4c). To the solution of [1- (morpholinomethyl)cyclopropyl]methanol (188.41 mg, 1.10 mmol) in THF (8 mL) was added Lithium Bis(Trimethylsilyl)Amide in THF (1.10 mL, 1.10 mmol) dropwise at -70 ℃ under N2 . The mixture was stirred at -70 ℃ for 30 min, and then O1-tert-butyl O3-methyl (3R)-4-(6-chloro- 2-methylsulfonyl-5-nitro-pyrimidin-4-yl)piperazine-1,3-dicarboxylate (4b, 480.00 mg, 1.00 mmol) was added in one portion. The resulting mixture was stirred at the -70 ℃ for 2h before 2- aminospiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile;methanesulfonic acid (Int 2, 383.38 mg, 1.20 mmol) was added, followed by the addition of DIPEA (388.11 mg, 3.00 mmol). The reaction was allowed to warm to r.t and stirred overnight. The mixture was quenched with NH4Cl aqueous and extracted with EtOAc (20 mLx3). The combined extracts were washed with water and brine, dried (Na2SO4), and concentrated in vacuo. The residue was purified by FCC (silica[6-(2-amino-3-cyano-spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-1'-yl)-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]-5-nitro-pyrimidin-4-yl]piperazine-1,3-dicarboxylate (4c, 495.00 mg, 0.65 mmol, 65.30% yield) as a brown solid. LCMS calculated for C33H44N9O8S2 (M+H)+m / z = 758.28; found: 758.6.

[0331] Step 4. Synthesis of tert-butyl (6aR)-4-(2-amino-3-cyano-spiro[6H-thieno[3,4- b]thiophene-4,3'-azetidine]-1'-yl)-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]-6-oxo- 6a,7,9,10-tetrahydro-5H-pyrazino[2,1-h]pteridine-8-carboxylate (4d). To the solution of O1-tert- butyl O3-methyl (3R)-4-[6-(2-amino-3-cyano-spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-1'- yl)-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]-5-nitro-pyrimidin-4-yl]piperazine-1,3- dicarboxylate (4c, 100.00 mg, 0.13 mmol) in Ethanol (2 mL) was added Fe powder (147.38 mg, 2.64 mmol) and AcOH (0.3 mL, 5.28 mmol) at room temperature under N2. The mixture was stirred at 60 ℃ for 3 h. The reaction was cooled and filtered. The filtrates were concentrated to dryness and the residue was diluted with EtOAc (30 mL) and the organic layer was washed with saturated NaHCO3solution, water followed by brine. The organics layer was dried (MgSO4) and concentration to dryness. The residue was purified by FCC (silica gel, eluting with MeOH in DCM 0% to 10%, v / v) to afford tert-butyl (6aR)-4-(2-amino-3-cyano-spiro[6H-thieno[3,4-b]thiophene- 4,3'-azetidine]-1'-yl)-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]-6-oxo-6a,7,9,10- tetrahydro-5H-pyrazino[2,1-h]pteridine-8-carboxylate (4d, 70.00 mg, 0.10 mmol, 76.24% yield) as a yellow solid. LCMS calculated for C48H54FN10O4S (M+H)+m / z = 696.28; found: 696.3.

[0332] Step 5. Synthesis of 2-amino-1'-[(6aR)-2-[[1- (morpholinomethyl)cyclopropyl]methoxy]-6-oxo-5,6a,7,8,9,10-hexahydropyrazino[2,1- h]pteridin-4-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile (Compound 4). To the solution of tert-butyl (6aR)-4-(2-amino-3-cyano-spiro[6H-thieno[3,4-b]thiophene-4,3'- azetidine]-1'-yl)-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]-6-oxo-6a,7,9,10-tetrahydro- 5H-pyrazino[2,1-h]pteridine-8-carboxylate (70 mg, 0.10 mmol) in DCM (1.5 mL) was added trifluoroacetic acid (0.5 mL, 6.49 mmol). The reaction was stirred at room temperature for 2 h. The solvent was removed and the residue was purified by prep-HPLC to afford 2-amino-1'- [(6aR)-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]-6-oxo-5,6a,7,8,9,10- hexahydropyrazino[2,1-h]pteridin-4-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3- carbonitrile (Compound 4, 36.42 mg, 0.06 mmol, 59.57% yield) as a white solid. LCMS calculated for C27H34N9O3S2(M+H)+m / z =596.22; found: 596.2.1H NMR (400 MHz, DMSO- d6) δ 9.38 (s, 1H), 7.35 (s, 2H), 4.77 (d, J = 9.2 Hz, 1H), 4.53-4.57 (m, 2H), 4.24 (d, J = 9.2 Hz, 1H), 3.97 – 4.19 (m, 5H), 3.66 (dd, J = 10.8, 3.6 Hz, 1H), 3.55 (t, J = 4.4 Hz, 4H), 3.21 (dd, J = 12.4, 3.2 Hz, 1H), 2.90 (d, J = 11.6 Hz, 1H), 2.52 - 2.70 (m, 3H), 2.30 – 2.43 (m, 4H), 2.25 (s, 2H), 0

[0333] Compound 5. 2-amino-1'-[(6aS)-2-[[1-(morpholinomethyl)cyclopropyl]methoxy]-6- oxo-5,6a,7,8,9,10-hexahydropyrazino[2,1-h]pteridin-4-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'- azetidine]-3-carbonitrile

[0334] Compound 5 was prepare3. LCMS calculated for C27H34N9O3S2 (M+H)+m / z =596.22; found: 596.2.1H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 7.35 (s, 2H), 4.77 (d, J = 9.2 Hz, 1H), 4.53-4.57 (m, 2H), 4.24 (d, J = 9.2 Hz, 1H), 4.02 – 4.19 (m, 5H), 3.66 (dd, J = 10.8, 3.6 Hz, 1H), 3.55 (t, J = 4.8 Hz, 4H), 3.21 (dd, J = 12.4, 3.2 Hz, 1H), 2.90 (d, J = 11.2 Hz, 1H), 2.54 – 2.69 (m, 3H), 2.31 – 2.42 (m, 4H), 2.25 (s, 2H), 0.56 (t, J = 4.8 Hz, 2H), 0.35 (t, J = 4.8 Hz, 2H).

[0335] Compound 6.2-amino-1'-[rac-(1R,14S)-9-[[1- (morpholinomethyl)cyclopropyl]methoxy]-5-oxo-4-oxa-8,10,12,17- tetrazatetracyclo[12.2.1.02,12.06,11]heptadeca-6(11),7,9-trien-7-yl]spiro[6H-thieno[3,4- b]thiophene-4,3'-azetidine]-3-carbonitrile

[0336] Compound 6 was prepared similarly to that of Ex.2. LCMS calculated for C30H37N8O4S2 (M+H)+m / z =637.24; found: 637.3.1H NMR (400 MHz, CD3OD) δ 4.90 – 5.00 (m, 1H), 4.65 – 4.81 (m, 2H), 3.93 –4.50 (m, 9H), 3.66 (t, J = 4.8 Hz, 4H), 3.45 – 3.54 (m, 1H), 3.34 – 3.45 (m, 1H), 2.88 – 3.09 (m, 1H), 2.48 (s, 4H), 2.38 (s, 2H), 1.54 – 2.05 (m, 4H), 0.65 (t, J = 5.2 Hz, 2H), 0.44 (t, J = 5.2 Hz, 2H).

[0337] Compound 7.2-amino-1'-[rac-(1R,13S)-8-[[1- (morpholinomethyl)cyclopropyl]methoxy]-3-oxo-4,7,9,11,16- pentazatetracyclo[11.2.1.02,11.05,10]hexadeca-5(10),6,8-trien-6-yl]spiro[6H-thieno[3,4- b]thiophene-4,3'-azetidine]-3-carbonitrile

[0338] Compound 7 was prepare 3. LCMS calculated for C29H36N9O3S2(M+H)+m / z =622.24; found: 622.3.1H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1H), 7.36 (s, 2H), 4.84 (d, J = 9.2 Hz, 1H), 4.64 (d, J = 8.8 Hz, 1H), 4.45 (d, J = 8.8 Hz, 1H), 4.14 (d, J = 2.8 Hz, 1H), 4.11 (s, 1H), 3.98 – 4.09 (m, 3H), 3.79 – 3.85 (m, 1H), 3.72 – 3.78 (m, 2H), 3.48 – 3.58 (m, 5H), 3.31 (s, 1H), 2.83 (d, J = 10.8 Hz, 1H), 2.30 – 2.42 (m, 4H), 2.24 (s, 2H), 1.46 – 1.73 (m, 4H), 0.55 (t, J = 4.8 Hz, 2H), 0.34 (t, J = 4.8 Hz, 2H).

[0339] Compound 8.2-amino-1'-[(11S)-4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-8-oxo-9,13-dioxa-1,3,5-triazatricyclo[9.5.0.02,7]hexadeca- 2(7),3,5-trien-6-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile

[0340] Compound 8 was prepared similarly to that of Ex. 2. LCMS calculated for C28H33FN7O4S2(M+H)+m / z =614.73; found: 614.9.1H NMR (400 MHz, CD3OD) δ 5.26 (d, J = 52.5 Hz, 1H), 5.03 – 4.88 (m, 1H), 4.86 – 4.31 (m, 5H), 4.24 – 3.88 (m, 8H), 3.68 – 3.39 (m, 2H), 3.28 – 3.06 (m, 4H), 3.02 – 2.92 (m, 1H), 2.34 – 1.76 (m, 8H).

[0341] Compound 9. 2-amino-1'-[4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-9-oxo-1,3,5,8,13-pentazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-trien-6-yl]spiro[6H- thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile

[0342] Compound 9 was prepared similarly to that of Ex. 3. LCMS calculated for C27H33FN9O2S2 (M+H)+m / z =598.22; found:598.5.1H NMR (400 MHz, CD3OD) δ 5.26 (d, J = 54.7 Hz, 1H), 4.80 – 4.70 (m, 2H), 4.55 (d, J = 9.7 Hz, 1H), 4.43 (d, J = 9.8 Hz, 1H), 4.17 – 4.08 (m, , . , , . . , , . . , , . . , H), 3.16 – 3.11 (m, 1H), 3.02 – 2.69 (m, 7H), 2.44 – 2.05 (m, 4H), 2.01 – 1.73 (m, 3H).

[0343] Example 4. Exemplary synthesis of 2-amino-1'-[(10R)-4-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9-oxo-11-oxa-1,3,5,8- tetrazatricyclo[8.3.1.02,7]tetradeca-2(7),3,5-trien-6-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'- azetidine]-3-carbonitrile (Compound 10) [0] ep . yn es s o ( )- -( -( -am no- -cyano- -sp ro[aze ne- , - eno[3,4- b]thiophen]-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5- nitropyrimidin-4-yl)morpholine-2-carboxylate (10a). To the solution of 2,4,6-Trichloro-5- nitropyrimidine (150.0 mg, 0.66mmol) and DIEA (339.49 mg, 2.63 mmol) in DCM (8 mL) was added the solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (115.0 mg, 0.72mmol) in DCM (2 mL) slowly at -70 ℃ under Ar. The mixture was stirred at same temperature for 1h and then allowed to warm to 0 ℃ and stirred for 1h. It was cooled to -70 ℃ again and methyl (2R)-morpholine-2-carboxylate (95.0 mg, 0.66 mmol) was added. The whole mixture was allowed to warm to RT and stirred for 16 h. To this reaction mixture, 2- aminospiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile methanesulfonic acid salt (314.6 mg, 0.99 mmol) was added and stirred for 2 h. The reaction mixture was concentrated and purified by flash column chromatography (silica gel, eluting with 0 to 10% MeOH in DCM). The desired fractions were concentrated to dryness in vacuo to afford methyl (2R)-4-[6-(2-amino-3- cyano-spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-1'-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5-nitro-pyrimidin-4-yl]morpholine-2-carboxylate (350.0 mg, 0.433 mmol, 65.93 % yield) as a yellow oil. LCMS calculated for C27H32FN8O6S2 (M+H)+m / z =647.19; found: 648.0.

[0345] Step 2. Synthesis of methyl(R)-4-(5-amino-6-(2'-amino-3'-cyano-6'H-spiro[azetidine- 3,4'-thieno[3,4-b]thiophen]-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)me(2-amino-3-cyano-spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-1'-yl)-2-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5-nitro-pyrimidin-4-yl]morpholine-2-carboxylate (300.0 mg, 0.37mmol) in Ethanol (5 mL) was added Iron powder (414.5 mg, 7.42 mmol) and AcOH (0.85 mL, 14.84 mmol) at RT. The mixture was heated to 60℃ and stirred for 5 h. LCMS showed the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated to dryness and the residue was taken up in EtOAc (20 ml) and washed with water (2 x 20 ml) followed by saturated brine (20 ml). The organics were then separated and dried (MgSO4) before concentration to dryness. The crude was then purified by flash column chromatography (silica gel, eluting with 0 to 10% MeOH in DCM). The desired fractions were concentrated to dryness in vacuo to get methyl (2R)-4-[5-amino-6-(2-amino-3-cyano-spiro[6H-thieno[3,4- b]thiophene-4,3'-azetidine]-1'-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrimidin-4-yl]morpholine-2-carboxylate (130.0 mg, 0.211 mmol, 56.80 % yield) as yellow solid. LCMS calculated for C27H34FN8O4S2 (M+H)+m / z = 617.22; found:618.0.

[0346] Step 3. Synthesis of (R)-4-(5-amino-6-(2'-amino-3'-cyano-6'H-spiro[azetidine-3,4'- thieno[3,4-b]thiophen]-1-yl)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)pyrimidin-4-yl)morpholine-2-carboxylic acid (10c). To the mixture of methyl (2R)-4- [5-amino-6-(2-amino-3-cyano-spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-1'-yl)-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4-yl]morpholine-2- carboxylate (65.0 mg, 0.11 mmol) in Methanol (2 mL), Water (1 mL) and THF (2 mL) was added the solution of NaOH (2.0 mL, 2.0 mmol, 1mol / L) at RT under N2. The whole mixture was stirred for 2 h. The solvent was removed under reduced pressure and the resulting aqueous solution was neutralized to PH=7 using HCl (1M). The reaction mixture was purified by prep-HPLC (eluent with MPA: Water with 0.1% NH4HCO3, MPB: ACN , 5%-60% MPB) to afford the title product (2R)-4-[5-amino-6-(2-amino-3-cyano-spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-1'-yl)-2- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrimidin-4-yl]morpholine-2- carboxylic acid (20 mg, 0.0332 mmol, 31.49 % yield) as a colorless oil. LCMS calculated for C26H32FN8O4S2(M+H)+ m / z =603.20; found: 603.2.

[0347] Step 4. Synthesis of 2-amino-1'-[(10R)-4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-9-oxo-11-oxa-1,3,5,8-tetrazatricyclo[8.3.1.02,7]tetradeca- 2(7),3,5-trien-6-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile (Compound 10). To the mixture of (2R)-4-[5-amino-6-(2-amino-3-cyano-spiro[6H-thieno[3,4-b]thiophene- 4,3'-azetidine]-1'-yl)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrimidin-4-yl]morpholine-2-carboxylic acid (20.0 mg, 0.03 mmol) in DMF (5 mL) was added HATU (25.2 mg, 0.07 mmol) and DIEA (21.4 mg, 0.17 mmol) at RT under N2. The wholeWater with 0.1% NH4HCO3, B: ACN, 5%-60%B) to afford 2-amino-1'-[(10R)-4-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-9-oxo-11-oxa-1,3,5,8- tetrazatricyclo[8.3.1.02,7]tetradeca-2(7),3,5-trien-6-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'- azetidine]-3-carbonitrile (6.23 mg, 0.0104 mmol, 31.4% yield) as a white solid. LCMS calculated for C26H30FN8O3S2 (M+H)+m / z =585.19; found:585.8.1H NMR (400 MHz, CD3OD) δ 5.28 (d, J = 55.2 Hz, 1H), 4.94 (d, J = 9.9 Hz, 1H), 4.78 (d, J = 9.5 Hz, 1H), 4.56 (d, J = 9.8 Hz, 1H), 4.40 (d, J = 3.6 Hz, 1H), 4.34 (d, J = 9.9 Hz, 1H), 4.19 (d, J = 10.6 Hz, 1H), 4.06 (s, 2H), 4.00 (d, J = 10.6 Hz, 1H), 3.80 (d, J = 13.4 Hz, 1H), 3.70 – 3.61 (m, 2H), 3.56 – 3.45 (m, 1H), 3.36 – 3.33 (m, 1H), 3.29 – 3.15 (m, 4H), 3.05 – 2.95 (m, 1H), 2.34 – 1.82 (m, 6H).

[0348] Compound 11. 2-amino-1'-[4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-9-oxo-11-oxa-1,3,5,8-tetrazatricyclo[8.4.1.02,7]pentadeca-2(7),3,5-trien-6- yl]spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile

[0349] Compound 11 was prepared s m ary to that of Ex. 4. LCMS calculated for C27H32FN8O3S2 (M+H)+m / z = 599.19; found: 599.2.1H NMR (400 MHz, CD3OD) δ 5.24 (d, J = 55.2 Hz, 1H), 4.82 – 4.75 (m, 2H), 4.60 – 4.51 (m, 2H), 4.42 (d, J = 6.0 Hz, 1H), 4.32 (d, J = 9.2 Hz, 1H), 4.13 (dd, J = 10.4, 2.4 Hz, 1H), 4.14 (s, 2H), 4.08 – 3.87 (m, 3H), 3.75 (t, J = 12.0 Hz, 1H), 3.57 (d, J = 15.6 Hz, 1H), 3.27 – 3.12 (m, 3H), 3.02 – 2.87 (m, 2H), 2.35 – 2.05 (m, 3H), 2.03 – 1.77 (m, 4H), 1.54 (d, J = 14.8 Hz, 1H).

[0350] Example 5. Exemplary synthesis of 2-amino-1'-[(1S)-4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-8,12-dioxa-1,3,5-triazatricyclo[8.5.0.02,7]pentadeca- 2(7),3,5-trien-6-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile (Compound 12)

[0351] Step 1. Synthesis of (2R,8S)-8-[(4,6-dichloro-5-iodo-pyrimidin-2-yl)oxymethyl]-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizine (12a). To a solution of [(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methanol (0.431 g, 2.71 mmol, 1.05 eq) in THF (10 mL) was added LiHMDS (3.1 mL, 3.1 mmol, 1.2 eq) at -70 ℃ under N2. After it was stirred for 1h at the same temperature, 4,6-dichloro-5-iodo-2-methylsulfonyl-pyrimidine (1.14 g, 2.58 mmol, 1 eq) was added and stirred for 1.5h at same temperature. The reaction mixture was quenched with saturated NH4Cl solution (10 mL) and then extracted with EtOAc (20 mL). The extract was washed with water (20 mL) followed by saturated brine (20 mL). It was dried (Na2SO4) and concentrated in vacuo to give the residue. It was purified by flash column chromatography (silica gel, eluting with 0~100% EtOAc in PE) to afford (2R,8S)-8-[(4,6-dichloro-5-iodo-pyrimidin-2-yl)oxymethyl]-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizine (810 mg, 1.87 mmol, 72.5 % yield) as a light yellow solid. LCMS calculated for C12H14Cl2FIN3O (M+H)+m / z =431.95; found:432.3 / 434.2.

[0352] Step 2. Synthesis of ((R)-4-(6-chloro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-5-iodopyrimidin-4-yl)-1,4-oxazepan-3-yl)methanol (12b). To a solution of (2R,8S)-8-[(4,6-dichloro-5-iodo-pyrimidin-2-yl)oxymethyl]-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizine (500 mg, 1.16 mmol, 1 eq ) in DMSO (5 mL) were added (R)-(1,4- oxazepan-3-yl)methanol (182 mg, 1.11 mmol, 0.9 eq) followed by DIEA (448 mg, 3.47mmol, 3 eq) at RT under N2. The reaction mixture was stirred for 3h. LCMS showed the reaction nearly completed. It was diluted with H2O (30 mL) and then extracted with EtOAc (30 mL*2). The combined extracts were washed with saturated brine (30 mL) and dried (Na2SO4). It was then concentrated in vacuo to give the residue and purified by flash column chromatography (silica gel, eluting with 0~10% MeOH in DCM) to afford ((R)-4-(6-chloro-2-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-5-iodopyrimidin-4-yl)-1,4-oxazepan-3-yl)methanol (345 mg, 0.655 mmol, 56.6% yield) as a yellow oil. LCMS calculated for C18H26ClFIN4O3 (M+H)+m / z =527.07; found: 527.2 / 529.2

[0353] Step 3. Synthesis of (1S)-6-chloro-4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-8,12-dioxa-1,3,5-triazatricyclo[8.5.0.02,7]pentadeca- 2(7),3,5-triene (12c). The mixture of [(4S)-4-[6-chloro-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5-iodo-pyrimidin-4-yl]-1,4-oxazepan-3-yl]methanol (100 mg, 0.19 mmol, 1 eq), CuI (3.62 mg, 0.02 mmol, 0.1 eq), o-Phenanthroline (6.84 mg, 0.04 mmol, 0.2 eq) and cesium carbonate (86.6 mg, 0.27 mmol, 1.4 eq) in toluene (5 mL) was heated to 110℃ overnight under N2. LCMS showed the reaction was completed. The reaction mixture was filtered, and the filtrate was concentrated in vacuo to give the residue. It was diluted with H2O (20 mL) and extracted with EtOAc (20 mL*2). The combined extracts were washed with saturated brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give the residue. It was purified by flash column chromatography (silica gel, eluting with 10% MeOH in DCM) to afford (1S)-6-chloro-4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8,12- dioxa-1,3,5-triazatricyclo[8.5.0.02,7]pentadeca-2(7),3,5-triene (65 mg, 0.163 mmol, 85.8% yield) as a brown oil. LCMS calculated for C18H25ClFN4O3 (M+H)+m / z =399.16; found: 399.4 / 401.4

[0354] Step 4. Synthesis of 2'-amino-1-((S)-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-6a,7,10,11-tetrahydro-6H,9H-pyrimido[4',5':5,6][1,4]oxazino[3,4- c][1,4]oxazepin-4-yl)-6'H-spiro[azetidine-3,4'-thieno[3,4-b]thiophene]-3'-carbonitrile (Compound 12). The mixture of (1S)-6-chloro-4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-8,12-dioxa-1,3,5-triazatricyclo[8.5.0.02,7]pentadeca- 2(7),3,5-triene (65 mg, 0.16 mmol, 1eq), 2-aminospiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]- 3-carbonitrile (182 mg, 0.81 mmol, 5 eq) and CsF (78 mg, 0.49 mmol, 3 eq) in DMSO (0.5 mL) was heated to 110 ℃ for 2 h. It was diluted with DCM / MeOH (10 / 1, 10 mL) and washed with H2O (10 mL). The aqueous layer was extracted back with DCM / MeOH (10 mL, 10 / 1). The combined extracts was washed with saturated brine (10 mL), dried (Na2SO4) and concentrated in vacuo to give the residue. It was purified by flash column chromatography (silica gel, eluting with 15% MeOH in DCM) to afford crude product. And then it was purified by prep-HPLC (MPA: Water with 0.1% NH4HCO3, MPB: ACN with 0.1% NH4HCO3, 50% MPB) to afford 2-amino-1'-[(1S)- 4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-8,12-dioxa-1,3,5- triazatricyclo[8.5.0.02,7]pentadeca-2(7),3,5-trien-6-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'- azetidine]-3-carbonitrile (36.82 mg, 0.0606 mmol, 37.2% yield) as a light yellow solid. LCMS calculated for C27H33FN7O3S2 (M+H)+m / z =586.21; found: 586.9.1H NMR (400 MHz, CD3OD) δ 5.26 (d, J = 54.8 Hz, 1H), 4.79-4.69 (m, 2H), 4.62-4.51 (m, 1H), 4.44-4.30 (m, 2H), 4.12-4.06(m, 1H), 4.03 (s, 2H), 3.98-3.89 (m, 4H), 3.87-3.79 (m, 1H), 3.74-3.65 (m, 2H), 3.63-3.54 (m, 1H), 3.28-3.10 (m, 4H), 3.02-2.92 (m, 1H), 2.34-2.07 (m, 3H), 2.06-1.77 (m, 5H).

[0355] Compound 13.2-amino-1'-[(12S)-2-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-6-oxo-5,6a,7,9,10,11-hexahydro-[1,4]oxazepino[3,4- h]pteridin-4-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile

[0356] Compound 13 was prepathat of Ex. 3. LCMS calculated for C27H32FN8O3S2 (M+H)+m / z =599.2 ; found: 599.7.1H NMR (400 MHz, CD3OD) δ 5.29 (d, J = 54.8 Hz, 1H), 4.94-4.88 (m, 1H), 4.65 (s, 2H), 4.48-4.39 (m, 1H), 4.32 (d, J = 9.6 Hz, 1H), 4.21- 4.12 (m, 2H), 4.11-4.00 (m, 3H), 3.97-3.86 (m, 2H), 3.81-3.72 (m, 1H), 3.49-3.39 (m, 1H), 3.28- 3.10 (m, 4H), 3.08-2.96 (m, 1H), 2.39-2.09 (m, 4H), 2.04-1.78 (m, 4H)

[0357] Compound 14. 2-amino-1'-[4-[[1-(morpholinomethyl)cyclopropyl]methoxy]-9-oxo- 1,3,5,8,13-pentazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5-trien-6-yl]spiro[6H-thieno[3,4- b]thiophene-4,3'-azetidine]-3-carbonitrile

[0358] Compound 14 was prepared similarly to that of Ex. 3. LCMS calculated for C28H36N9O3S2(M+H)+m / z =610.2; found:610.8.1H NMR (400 MHz, CD3OD) δ 4.78-4.72 (m, 2H), 4.55 (d, J = 9.5 Hz, 1H), 4.43 (d, J = 10.0 Hz, 1H), 4.22 (ABq, J=10.8 Hz, 2H), 4.05 (s, 2H), 3.98-3.88 (m, 1H), 3.75-3.63 (m, 5H), 3.00-2.73 (m, 6H), 2.56-2.42 (m, 4H), 2.40-2.30 (m, 1H), 2.38 (s, 2H), 0.64 (t, J = 5.2 Hz, 2H), 0.43 (t, J = 5.2 Hz, 2H).

[0359] Compound 15.2-amino-1'-[(11S)-4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-8-oxa-1,3,5,13-tetrazatricyclo[9.4.0.02,7]pentadeca-2(7),3,5- trien-6-yl]spiro[6H-thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile

[0360] Compound 15 was prepthat of Ex. 5. LCMS calculated for C27H34FN8O2S2(M+H)+m / z =585.22, found:585.7.1H NMR (400 MHz, CD3OD) δ 5.28 (d, J = 54.1 Hz, 1H), 4.81 – 4.55 (m, 3H), 4.42 (t, J = 10.5 Hz, 2H), 4.04 (s, 2H), 4.19 – 3.92 (m, 5H), 3.80 – 3.69 (m, 1H), 3.27 – 3.08 (m, 4H), 3.06 – 2.93 (m, 2H), 2.92 – 2.79 (t, J = 11.2 Hz, 1H), 2.64 (t, J = 11.2 Hz, 1H), 2.36 – 2.06 (m, 4H), 2.05 – 1.77 (m, 4H).

[0361] Compound 16. 2-amino-1'-[4-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-8,11-dioxa-1,3,5-triazatricyclo[8.4.1.02,7]pentadeca-2(7),3,5-trien-6-yl]spiro[6H- thieno[3,4-b]thiophene-4,3'-azetidine]-3-carbonitrile

[0362] Compound 16 was prepared similarly to that of Ex. 5. LCMS calculated for C27H34FN7O3S2 (M+H)+m / z =586.2, found:586.4. Example 6: Nucleotide Exchange Assay:

[0363] Ras proteins cycle between an active, GTP bound state, and an inactive GDP-bound state. This activity is tightly regulated by GTPase activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs). GEFs, such as SOS1 / 2, activate Ras proteins by exchanging GDP for GTP, thus returning Ras to its active conformation (Simanshu, Nissley, & McCormick, 2017). Therefore, a small molecule that binds K-Ras in a manner that prevents SOS-mediated nucleotide exchange locks KRas in its inactive state. Homogenous time resolved fluorescence (HTRF) was used to detect SOS-mediated binding of a fluorescent GTP analog, GTP-DY-647P1 (Jena Biosciences NU-820-647P1) to GST-tagged KRAS-G12D (2-169) or to GST-tagged KRAS- G12V (2-169, Reaction Biology, MSC-11-540). GST-tagged KRAS-G12D (2-169) and anti-GST MAb Tb Cryptate Gold (CisBio 61GSTTLB) were diluted into assay buffer (20 mM HEPES, pH 7.3, 150 mM NaCl 5 mM MgCl2005% BSA 00025% NP40 1 mM DTT) to prepare a 25Xdonor solution.5X compound was added to the protein mixture and incubated for 1 h at RT.2.5X acceptor solution containing SOS1cat (564-1049, Reaction Biology MSC-11-502) and GTP-DY- 647P1 were then added to the donor KRAS mixture such that the final concentration of the reaction contained 0.25 nM GST-tagged KRAS-G12D (2-169), 20 nM SOScat, and 150 nM GTP-DY- 647P1. The reaction was monitored using at RT with the Envision multimode plate reader (Ex / Em 337 / 665, 620 nM) up to 90 minutes at 5 minute intervals. To monitor KRAS-G12V SOS-mediated nucleotide exchange, 80 nM SOS was added to reaction instead of 20 nM. All other components were the same as previously described. Data was blanked to reactions without SOS1 and % inhibition was calculated such that DMSO only = 0% and blank = 100%. Curve fitting was done using a 4 parameter fit. Reported IC50values were extracted at 30 min and 90 min for the KRAS- G12D and KRAS-G12V assays, respectively. NEA KRAS G12D and G12V IC50(uM) values of selected compounds are depicted in Table 1 with compounds having a value <0.01 uM as ++++; ≥ 0.01 uM to 0.1 uM as +++; ≥ 0.1 uM to 1 uM as ++; ≥ 1 uM to 20 uM as +; and ≥ 20 uM as NA. Example 7. pERK In Cell Western (ICW) assay

[0364] pERK ICW is a high throughput screening assay to evaluate the cellular potency of mutant KRAS small molecule inhibitors. KRAS mutant cell lines GP2D (KRAS-G12D) and SW620 (KRAS-G12V) were purchased from ATCC and maintained respectively in RPMI / DMEM / RPMI medium supplemented with 10% fetal bovine serum.

[0365] Cells grown in exponential phase were trypsinized, resuspended in fresh media, and viable cells were counted using a cell counter with Trypan Blue (BioRad TC20). Cells were seeded into 384-well plate (Greiner 781091) at density of 10,000 cells / well for GP2D / SW620 and allowed to grow overnight in a 37˚C CO2 incubator. The next day, compounds were dispensed into wells with a ½ log, 9-point serial dilution using a Tecan D300e dispenser and incubated for 3 hours in a 37 ˚C CO2 incubator. Cells were then fixed with paraformaldehyde (Electron Microscopy Sciences, 15710, 4% final concentration) for 30 min, permeabilized with wash buffer (1X PBS + 0.1% Triton X-100) for 30 min and blocked with Odyssey blocking buffer (Li-COR 927-70001) for 1 hour, all at room temperature (RT). Phospho-ERK antibody (CST 4370L) was diluted 1:500 in Odyssey T20 (PBS) antibody diluent (Li-COR 927-75001) and incubated with cells overnight at 4 ˚C. The next day, plates were washed 5x with wash buffer, incubated with IRDye 800 CW, Goat anti-Rabbit secondary antibody (Li-COR 926-32211, 1:800) and DRAQ5 (CST 4084L, 1:5,000) diluted in in Odyssey T20 (PBS) antibody diluent for 1 hour, washed 5x, and imaged on an Odyssey CLx imaging system.

[0366] For data analysis, signal intensities from 800 (phosphor-ERK) and 700 (DRAQ5) channwell and percent of blank control values were computed. Data were then imported into Graphpad Prism to compute half-maximal inhibitory concentrations (IC50) using a 4-parameter variable slope model. Z-factor for each plate was computed from signals derived from wells treated with either DMSO or 5 µM of control compound.

[0367] Table 1 includes NEA KRAS G12D and G12V IC50 (uM) values (< 0.01 uM as ++++; ≥ 0.01 uM to 0.1 uM as +++; ≥ 0.1 uM to 1 uM as ++; ≥ 1 uM to 20 uM as +; and ≥ 20 uM as NA), of selected compounds; ND indicates not determined, and GP2D / SW620 pERK ICW IC50(uM) values ≥ 0.001 uM to 0.01 uM as ++++; ≥ 0.01 uM to 0.1 uM as +++; ≥ 0.1 uM to 1 uM as ++; ≥ 1 uM to 10 uM as + and ≥ 10 uM as NA. Table 1: NEA KRAS G12D and G12V IC50 (uM) values NEA-G12D NEA-G12V Compound M M

[0368] While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention.It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I): Formula (I), or a pharmaceutically accepta n:X is , and wherein t represents the point of connection between X and Y; A is5- to 15-membered heterocycle and C5-C12 carbocycle, wherein the 5- to 15- membered heterocycle and C5-C12 carbocycle are each optionally substituted with one or more substituents independently selected from R50; each R50is selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), -S(O)2N(R20)2, - S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, -C(=NR20)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, - NHCN, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-C12 carbocycle and 5- to 12-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, - NHCN, C1-6alkyl-N(R20)2, C1-6alkyl-SO2R20, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 5- to 12- membered heterocycle and C3-C12 carbocycle, wherein the 5- to 12-membered heterocycle and C3-C12 carbocycle are each optionally substituted independently with one or more R2*; each R2*is independently selected from halogen, -B(OR20)2, -OR20, -SR20, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -C(O)N(R20)2, - C(O)NR20OR20, -N(R20)C(O)R20, -N(R20)C(O)N(R20)2, -N(R20)C(O)OR20, -N(R20)2, - C(O)R20, -C(O)OR20, -OC(O)R20, -OC(O)N(R20)2, -NO2, =O, =N(R20), =NO(R20), -CN, -hydroxyalkyl, C1-6cyanoalkyl, C1-6haloalkyl, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, 5- to 12- membered heterocycle and C3-C12 carbocycle; B is selected from a 7- to 15-membered fused heterocycle and C7-C15 fused carbocycle, wherein the 7- to 15-membered fused heterocycle and C7-C15fused carbocycle are each optionally substituted with one or more substituents independently selected from halogen, -CN, -NO2, =O, -N(R21)2, -B(OR21)2, -OR21, -SR21, -S(O)2(R21), -S(O)2N(R21)2, -NR21S(O)2R21, - C(O)N(R21)2, -C(O)NR21OR21, -N(R21)C(O)R21, -N(R21)C(O)N(R21)2, -N(R21)C(O)OR21, - C(O)R21, C(O)OR21, -OC(O)R21, -OC(O)N(R21)2, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 alkoxyalkyl, C1-6 hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, C2-6alkynyl, C3-C12carbocycle and 5- to 12-membered heterocycle; R2is selected from hydrogen, heterocycle, Cl-C6alkyl, -L-heterocycle, -L-N(R20)2, -L-OR20, -L- aryl, -L-heteroaryl, -L-cycloalkyl, -L-NHC(=NH)NH2, -L-C(O)N(R20)2, -L-Cl-C6 haloalkyl, -L-OR20, -L-NR20C(O)-aryl, -L-COOH, -L-NR20S(O)2(R20), -L-S(O)2N(R20)2, -L- N(R20)C(O)(OR20), -L-OC(O)N(R20)2, and -L-C(=O)OCl-C6alkyl, wherein the heterocycle, the heterocycle portion of -L-heterocycle, and the cycloalkyl portion of the -L-cycloalkyl are each optionally substituted with one or more R6, and wherein the aryl portion of -L- NR20C(O)-aryl, the aryl portion of -L-NR20C(O)-aryl, the aryl of the -L-aryl, and the heteroaryl of -L-heteroaryl are each optionally substituted with one or more R7; each R4is independently selected from halogen, -NO2, =O, =S, -CN, C1-6 alkyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6cyanoalkyl, C1-6hydroxyalkyl, and C1-6haloalkyl; n is selected from 0, 1, 2, 3, and 4; m is selected from 1 and 2; Y is selected from a bond, -O-, -S-, and -N(R5)-; each R5is independently selected from hydrogen and C1-C6 alkyl; each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, oxo, Cl-C3haloalkyl, Cl-C3alkyl-N3, C1-C3alkoxy, cyano, =CH2, =CHF, =CF2, =NO-Cl-C3alkyl, Cl-C3 aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q-phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3 alkyl substituted pyrazolyl, -C1-C3 alkyl-N(R5)2, -C(O)-C1-C3 alkyl-N(R5)2, -CH2OC(O)NCF3(R5), -CH2O-Cl-C6alkyl, -C(O)N(R5)2, tert- butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3alkoxy)Cl-C3alkyl-, (C1-C3alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Cl-C3 alkoxy, -CH2OC(O)N(R5)2, - CH2NHC(O)OC1-C6 alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6 alkyl, -CH2(pyrazolyl), -CH2NHSO2C1-C6alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, -OC(O)NH(C1-C3alkyl)O(C C alkyl) OC(O)NH(C C alkyl)O(C C alkyl)phenyl(C C alkyl)N(CH )OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl)phenyl, -OC(O)heterocycle, -O-Cl-C3alkyl, -O-Cl-C6haloalkyl, -C1-C3 alkyl-O-Cl-C6 haloalkyl, C1-6 alkyl-N(R20)2, -SF5, -S(O)2(R20), - S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, -(CH2)0-1S-heterocycle , - (CH2)0-1-O-heterocycle, -(CH2)0-1-O-phenyl, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, wherein the alkyl of -O-Cl-C3 alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; wherein the alkyl of -CH2O-Cl-C6alkyl is optionally substituted with one or more substituents selected from halogen and C3-C6carbocycle; wherein the heterocycle of -CH2heterocycle is optionally substituted with oxo; and wherein the phenyl of -(CH2)0-1-O-phenyl is optionally substituted with one or more substituents selected from C1-6alkyl, C1-6haloalkyl, SF5, C1-6alkyl-OR20, - OR20; wherein the heterocycle of -(CH2)0-1-O-heterocycle and -(CH2)0-1-S-heterocycle are each optionally substituted with one or more substituents selected from C1-6alkyl, C1-6 haloalkyl, C1-6 alkyl-OR20, and -OR20; each Q is selected from a bond, S, and O; each R7is independently selected from halogen, hydroxy, HC(=O)-, Cl-C4alkyl, Cl-C4alkoxy, Cl- C4haloalkyl, Cl-C4hydroxyalkyl, and -N(R5)2; each L is independently selected from a Cl-C4 alkylene optionally substituted with one or more substituents independently selected from hydroxy, Cl-C4 hydroxyalkyl, Cl-C4 alkyl, C3-C6 carbocycle, and 3- to 8-membered heterocycle, wherein the C3-C6carbocycle and 3- to 8- membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle or 3- to 8-membered heterocycle, wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6 hydroxyalkyl, and C1-6 haloalkyl; each R20is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen OH CN NO NHN(C1-6alkyl)2, C1-10alkyl, -C1-10haloalkyl, -O-C1-10alkyl, oxo, C3-12carbocycle, and 3- to 12-membered heterocycle; each R21is independently selected from hydrogen; and C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-12 carbocycle, and 3- to 12-membered heterocycle, each of which is optionally substituted with one or more substituents independently selected from halogen, -OH, -CN, -NO2, -NH2, - N(C1-6 alkyl)2, C1-10 alkyl, -C1-10 haloalkyl, -O-C1-10 alkyl, oxo, C3-12 carbocycle, and 3- to 12- membered heterocycle.

2. The compound or salt of claim 1, wherein each R6is independently selected from halogen, hydroxy, Cl-C3 hydroxyalkyl, Cl-C3 alkyl, oxo, Cl-C3 haloalkyl, C1-C3 alkoxy, cyano, =CH2, =NO-Cl-C3alkyl, Cl-C3aminoalkyl, -N(R5)S(O)2(R5), -Q-phenyl, -Q- phenylSO2F, -NHC(O)phenyl, - NHC(O)phenylSO2F, C1-C3alkyl substituted pyrazolyl, tert-butyldimethylsilyloxyCH2-, -N(R5)2, (C1-C3 alkoxy)Cl-C3 alkyl-, (C1-C3 alkyl)C(=O), oxo, (C1-C3 haloalkyl)C(=O)-, -SO2F, (C1-C3 alkoxy)Cl-C3 alkoxy, -CH2OC(O)N(R5)2, - CH2NHC(O)OC1-C6alkyl, -CH2NHC(O)N(R5)2, -CH2NHC(O)C1-C6alkyl, - CH2(pyrazolyl), -CH2NHSO2C1-C6 alkyl, -CH2OC(O)heterocycle, -OC(O)N(R5)2, - OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl), -OC(O)NH(C1-C3 alkyl)O(Cl-C3 alkyl)phenyl(C1- C3alkyl)N(CH3)2, -OC(O)NH(C1-C3alkyl)O(Cl-C3alkyl)phenyl, -OC(O)heterocycle, -O- Cl-C3 alkyl, -S(O)2(R20), -S(O)2N(R20)2, -S(O)N(R20)2, -S(O)R20(=NR20), -NR20S(O)2R20, and -CH2heterocycle, wherein the phenyl of -NHC(O)phenyl and -OC(O)NH(C1-C3 alkyl)(Cl-C3alkyl)phenyl are optionally substituted with one or more substituents selected from -C(O)H and OH, and wherein the alkyl of -O-Cl-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -CH2heterocyclyl is optionally substituted with oxo.

3. The compound or salt of claims 1 or 2, wherein X is bicyclic, tricyclic, or tetracyclic.

4. The compound or salt of any one of claims 1 to 3, wherein X is bicyclic.

5. The compound or salt of any one of claims 1 to 3, wherein X is tricyclic.

6. The compound or salt of any one of claims 1 to 3, wherein X is tetracyclic.

7. The compound or salt of any one of claims 1 to 6, wherein A is selected from 9- to 14- membered heterocycle, wherein the 9- to 14-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

8. The compound or salt of any one of claims 1 to 6, wherein A is selected from 9- to 13- membered heterocycle, wherein the 9- to 13-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

9. The compound or salt of any one of claims 1 to 6, wherein A is selected from 9- to 12- membered heterocycle, wherein the 9- to 12-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

10. The compound or salt of any one of claims 1 to 6, wherein A is selected from 9- membered heterocycle, wherein the 9-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

11. The compound or salt of any one of claims 1 to 6, wherein A is selected from 10- membered heterocycle, wherein the 10-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

12. The compound or salt of any one of claims 1 to 6, wherein A is selected from 11- membered heterocycle, wherein the 11-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

13. The compound or salt of any one of claims 1 to 6, wherein A is selected from 12- membered heterocycle, wherein the 12-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

14. The compound or salt of any one of claims 1 to 6, wherein A is selected from 13- membered heterocycle, wherein the 13-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

15. The compound or salt of any one of claims 1 to 6, wherein A is selected from 14- membered heterocycle, wherein the 14-membered heterocycle is optionally substituted with one or more substituents independently selected from R50.

16. The compound or salt of any one of claims 1 to 15, wherein the heterocycle of A is a fused heterocycle.

17. The compound or salt of any one of claims 1 to 15, wherein the heterocycle of A is a bridged heterocycle.

18. The compound or salt of any one of claims 1 to 15, wherein the heterocycle of A is a bridged heterocycle and a fused heterocycle.

19. The compound or salt of any one of claims 1 to 18, wherein the heterocycle of A has at least one oxygen atom.

20. The compound or salt of any one of claims 1 to 19, wherein the heterocycle of A has at least one nitrogen atom.

21. The compound or salt of any one of claims 1 to 20, wherein the heterocycle of A has at least one sulfur atom.

22. The compound or salt of any one of claims 1 to 21, wherein the heterocycle of A has at least one oxygen atom and one nitrogen atom23. The compound or salt of any one of claims 1 to 22, wherein the heterocycle of A has 3 heteroatoms.

24. The compound or salt of any one of claims 1 to 23, wherein X is selected from ,,, each of which is optionally substituted with one or m y selected from R50.

25. The compound or salt of any one of claims 1 to 24, wherein X is selected from e or26.h is 5027. The compound or salt of any one of claims 1 to 25, where hich is optionally substituted with one or more substituents ind50.

28. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents indep50rom R .

29. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents indeprom R50.

30. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents independently selected from R50. O 31. The compound or salt of any one of claims 1 to 25, where, which is optionally substituted with one or more substituents independently selected from R50.

32. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents indep from R50.

33. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents ind50from R .

34. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents indeprom R50.

35. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents independently selected from R50.

36. The compound or salt of any one of claims 1 to 25, where , whichis optionally substituted with one or more substituents independently selected from R50.

37. The compound or salt of any one of claims 1 to 25, where, which38. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents ind from R50.

39. The compound or salt of any one of claims 1 to 25, where h is optionally substituted with one or more substituents indep40. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents indrom R50.

41. The compound or salt of any one of claims 1 to 25, where hich is optionally substituted with one or more substituents independently selected from R50.

42. The compound or salt of any one of claims 1 to 25, where, which is optionally substituted with one or more substituents independently selected from R50.

43. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents indep d from R50.

44. The compound or salt of any one of claims 1 to 25, wherein X i hich is optionally substituted with one or more substituents independ50.

45. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents indepfrom R50.

46. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents independently selected from R50.

47. The compound or salt of any one of claims 1 to 25, where h isoptionally substituted with one or more substituents independently selected from R50.

48. The compound or salt of any one of claims 1 to 25, where, which is49. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents indep from R50.

50. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents indep50from R . O 51. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents indepfrom R50.

52. The compound or salt of any one of claims 1 to 25, where , which is optionally substituted with one or more substituents independently selected from R50.

53. The compound or salt of any one of claims 1 to 25, where h isoptionally substituted with one or more substituents independently selected from R50.

54. The compound or salt of any one of claims 1 to 25, where, which is optionally substituted with one or more substituents independently selected from R50.

55. The compound or salt of any one of claims 1 to 25, where h is optionally substituted with one or more substituents indep .

56. The compound or salt of any one of claims 1 to 55, wherein each R is independently selected from -CN, =O, -OH, C1-6 alkyl, -C(O)R20, -C(O)N(R20)2, C3-C6 carbocycle, 5- to 6-membered heterocycle, wherein the C1-6alkyl, C3-C6carbocycle, and 5- to 6-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -OR20, -N(R20)2, =O, -CN, - NHCN, 5- to 12-membered heterocycle and C3-C6carbocycle, wherein the 5- to 6- membered heterocycle and C3-C12carbocycle are each optionally substituted independently with one or more R2*; each R2*is independently selected from halogen, -OR20, -N(R20)2, -C(O)OR20, and C1-6hydroxyalkyl.

57. The compound or salt of any one of claims 1 to 56, wherein each R50is independently selected from -CN, =O, -OH, and C1-6 alkyl.

58. The compound or salt of any one of claims 1 to 57, wherein each R50is independently selected from =O, and C1-6alkyl.

59. The compound or salt of any one of claims 1 to 58, wherein each R50is independently selected from =O.

60. The compound or salt of any one of claims 1 to 59, wherein X is selected from,, , , ,O N and 61. T, 62. Ty , ,63. The compound or salt of any one of claims 1 to 62, wherein X is selected from , , 64. T, ,65.

66. The compound or salt of any one of claim .

67. The compound or salt of any one of claim .

68. The compound or salt of any one of claim .

69. The compound or salt of any one of claim .

70. The compound or salt of any one of claim .

71. The compound or salt of any one of claim .

72. The compound or salt of any one of claim.

73. The compound or salt of any one of claims 1 to 64, where .

74. The compound or salt of any one of claims 1 to 64, where .

75. The compound or salt of any one of claims 1 to 64, where .

76. The compound or salt of any one of claims 1 to 64, where .

77. The compound or salt of any one of claims 1 to 64, where .

78. The compound or salt of any one of claims 1 to 6, whereinX is selected from ,,HN , , ents i79. The compound or salt of any one of claims 1 to 6, wherein X is selected from h is opona y su s u e w one or more su s uen s n epen en y se ec e rom0.

80. The compound or salt of any one of claims 78 to 79, wherein each R50is independently selected from -CN, =O, C1-6 alkyl, -C(O)R20, -C(O)N(R20)2, C3-C6 carbocycle, 5- to 6- membered heterocycle, wherein the C1-6alkyl, C3-C6carbocycle, and 5- to 6-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -OR20, -N(R20)2, =O, -CN, -NHCN, 5- to 12-membered heterocycle and C3-C6carbocycle, wherein the 5- to 6-membered heterocycle and C3-C12 carbocycle are each optionally substituted independently with one or more R2*; each R2*is independently selected from halogen, -OR20, -N(R20)2, -C(O)OR20, and C1-6 hydroxyalkyl.

81. The compound or salt of any one of claims 1 to 2, or 80, wherein each R50is , 8 ,, , , ,,83. The compound or salt of any one of claims 1 to 2, wherein X is selected from and 84. TA), or a pharmaceutically acc85. The compound or salt of any one of claims 1 to 2, or 84, wherein A is selected from an optionally substituted 5- to 15-membered heterocycle.

86. The compound or salt of any one of claims 1 to 2, or 84, wherein A is selected from an optionally substituted 10- to 13-membered heterocycle.

87. The compound or salt of any one of claims 1 to 2, or 84, wherein A is selected from an optionally substituted 10-membered heterocycle.

88. The compound or salt of any one of claims 1 to 2, or 84, wherein A is selected from an optionally substituted 11-membered heterocycle.

89. The compound or salt of any one of claims 1 to 2, or 84, wherein A is selected from an optionally substituted 12-membered heterocycle.

90. The compound or salt of any one of claims 1 to 2, or 84, wherein A is selected from an optionally substituted 13-membered heterocycle.

91. The compound or salt of any one of claims 85 to 90, wherein the heterocycle has at least two oxygen atoms.

92. The compound or salt of any one of claims 85 to 91, wherein the heterocycle has at least93. The compound or salt of any one of claims 85 to 92, wherein the heterocycle of A is bicyclic or tricyclic.

94. The compound or salt of any one of claims 85 to 93, wherein the heterocycle of A is a fused heterocycle.

95. The compound or salt of any one of claims 85 to 94, wherein the heterocycle of A is a bridged heterocycle.

96. The compound or salt of any one of claims 84 to 94, wherein A is selected from h of wd from R50.

97. The compound or salt of any one of claims 1, or 85 to 94, wherein each R50is independently selected from -CN, =O, C1-6alkyl, -C(O)R20, -C(O)N(R20)2, C3-C5carbocycle, 5- to 6-membered heterocycle, wherein the C1-6 alkyl, C3-C5 carbocycle and 5- to 6-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -OR20, -N(R20)2, =O, -CN, -NHCN, 5- to 6- membered heterocycle and C3-C6 carbocycle, wherein the 5- to 6-membered heterocycle and C3- C6carbocycle are each optionally substituted independently with one or more R2*; each R2*is independently selected from halogen, -OR20, -N(R20)2, -C(O)OR20, C1-6hydroxyalkyl.

98. The compound or salt of claim 97, wherein each R50is independently selected from =O and C1-6alkyl.

99. The compound or salt of claim 1 or 98, wherein A is selected fro ,.

100. T A is selected from anoptionally substituted 5- to 13-membered heterocycle.

101. The compound or salt of any one of claims 1, or 84 to 92, wherein the heterocycle of A has at least one nitrogen atom.

102. The compound or salt of any one of claims 1, or 84 to 92, wherein the heterocycle of A has at least one oxygen atom.

103. The compound or salt of any one of claims 1, or 84 to 92, wherein the heterocycle of A has at least one sulfur atom.

104. The compound or salt of any one of claims 1, 84 to 92, or 100 to 103, wherein A is s ,, each of which is optionally substituted with one or m y selected from R50.

105. The compound or salt of any one of claims 1, 84 to 92, or 100 to 104, wherein each R50is independently selected from -CN, =O, C1-6 alkyl, -C(O)R20, -C(O)N(R20)2, C3-C5 carbocycle, 5- to 6-membered heterocycle, wherein the C1-6 alkyl, C3-C5 carbocycle and 5- to 6-membered heterocycle are each optionally substituted independently with one or more R1*; each R1*is independently selected from halogen, -OR20, -N(R20)2, =O, -CN, -NHCN, 5- to 6- membered heterocycle and C3-C6carbocycle, wherein the 5- to 6-membered heterocycle and C3- C6carbocycle are each optionally substituted independently with one or more R2*; each R2*is independently selected from halogen, -OR20, -N(R20)2, -C(O)OR20, C1-6 hydroxyalkyl.

106. The compound or salt of any one of claims 1, 84 to 92, or 100 to 105, wherein each R50is i , ,107. The compound or salt of any one of claims 1, 84 to 92, or 100 to 106, wherein A is s ,,, 108. The compound or salt of any one of claims 1, 84 to 92, or 100 to 107, wherein A is s, 1 ,, ,110. The compound or salt of any one of claims 1 to 109, wherein B is selected from an optionally substituted 8- to 15-membered fused heterocycle and optionally substituted C8- C15fused carbocycle.

111. The compound or salt of any one of claims 1 to 110, wherein B is selected fr,,, wherein each B is optionally substituted with one or more s 112. Te compound or sa t o any one of claims 1 to 111, wherein the one or more optional substituents of B, are independently selected at each occurrence from halogen, -CN, =O, -N(R21)2, -B(OR21)2, -OR21, -C(O)N(R21)2, -C(O)OR21, C1-6 hydroxyalkyl, C1-6 alkyl, and C2-6 alkynyl.

113. The compound or salt of any one of claims 1 to 112, wherein the one or more optional substituents of B, are independently selected at each occurrence from -CN, -NH2, -F, -Br, -Cl, C1-2alkyl, -OH, =O C2alkynyl, , -C(O)NH2, -B(OH)2, -C(O)OH, -OCH3, a 114.und or salt of any one of claims 1 to 113, wherein B is selected from , ,115. The compound or salt of any one of claims 1 to 114, wherein B is selected from an116. The compound or salt of claim 115, wherein the heterocycle of B has at least one sulfur atom.

117. The compound or salt of claim 116, wherein B is selected fro ,,, wherein each B is optionally substituted with one or more substituents.

118. The compound or salt of claim 117, wherein B is selected fro ,,119. The compound or salt of any one of claims 1 to 114, wherein B is selected from .

120. The compound or salt of any one of claims 1 to 114, where .

121. The compound or salt of any one of claims 1 to 114, where .

122. The compound or salt of any one of claims 1 to 121, where123. The compound or salt of any one of claims 1 to 121, wherein m is 2.

124. The compound or salt of any one of claims 1 to 123, wherein n is 0.

125. The compound or salt of any one of claims 1 to 123, wherein n is 1.

126. The compound or salt of claims 1 or 125, wherein R4is independently selected from halogen, =O, -CN, -OH, C1-6 alkyl, C2-6 alkynyl, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 cyanoalkyl, C1-6 hydroxyalkyl, and C1-6 haloalkyl.

127. The compound or salt of any one of claims 1, 7 to 23, wherein Formula (I) is represented byFormula (I-AA), or a pharmaceutically acceptable salt; wherein C is selected from a C5-C8carbocycle and 5- to 8-membered heterocycle, wherein the C5-C8carbocycle and 5- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -OMe, -N(R20)2, - C(O)R20, =O, -CN, -NHCN, C1-6 alkyl-N(R20)2, C1-6 aminoalkyl, C1-6 alkoxy, C1-6 hydroxyalkyl, C1-6c128. The compound or salt of any one of claims 1 to 83, wherein Formula (I) is represented by Formula (I-BB), or a pharmaceutically acceptablwherein C is selected from a C5-C8 carbocycle and 5- to 8-membered heterocycle, wherein the C5-C8 carbocycle and 5- to 8-membered heterocycle are each optionally substituted with one or more substituents independently selected from halogen, -OH, -OMe, -N(R20)2, - C(O)R20, =O, -CN, -NHCN, C1-6alkyl-N(R20)2, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6 cyanoalkyl, C1-6 haloalkyl, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl.

129. The compound or salt of any one of claims 127 to 128, wherein C is selected from and 1ach o131. The compound or salt of any one of claims 127 to 130, wherein C is selected from h isoptionally substituted.

132. The compound or salt of any one of claims 127 to 130, wherein C is optionally substituted with one or more substituents independently selected from halogen, -OH, - OMe, =O, -NH2, C1-6 haloalkyl, C1-6 alkyl, and C2-6 alkynyl.

133. The compound or salt of any one of claims 127 to 132, wherein C is optionally substituted with one or more substituents independently selected from halogen, and C1-6 alkyl.

134. The compound or salt of any one of claims 127 to 133, wherein C is selected from F F F , .

135. T.

136. Tof claims 127 to 133, wherein C is selected from . 137.of any one of claims 127 to 133, wherein C is selected from .

138. The compound or salt of any one of claims 127 to 133, wherein C is unsubstituted.

139. The compound or salt of any one of claims 1 to 138, Y is -O-.

140. The compound or salt of any one of claims 1 to 139, wherein L is selected from C1-C4 alkylene.

141. The compound or salt of claim 140, wherein L is selected from unsubstituted C1-C4alkylene.

142. The compound or salt of any one of claims 1 to 141, wherein L is selected from C1-C2 alkylene.

143. The compound or salt of claim 142, wherein L is selected from unsubstituted C1alkylene.

144. The compound or salt of claims 1 or 139, wherein each L is independently selected fromsame carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are each optionally substituted with one or more substituents selected from halogen, -OH, -NO2, =O, =S, -CN, C1-6aminoalkyl, C1-6alkoxy, C1-6hydroxyalkyl, C1-6haloalkyl.

145. The compound or salt of claim 144, wherein the optional substituents of L are selected from Cl-C4 hydroxyalkyl, Cl-C4 alkyl, C3-C6 carbocycle; and wherein optionally two substituents on the same carbon atom of L come together to form a C3-C6carbocycle or 3- to 8-membered heterocycle wherein the C3-C6 carbocycle and 3- to 8-membered heterocycle are optionally substituted with one or more substituents selected from halogen and C1-6haloalkyl.

146. The compound or salt of any one of claims 144 to 146, wherein L is selected from , a147. The compound or salt of claim 146, wherein L is selected from ,.

148. T, L is independently selected from a substituted Cl-C4 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3-C6 carbocycle 3- to 5-membered heterocycle.

149. The compound or salt of claim 148, wherein each L is independently selected from a substituted C2-3 alkylene, and wherein two substituents on the same carbon atom of L come together to form a C3 carbocycle or 4-membered heterocycle, wherein the C3 carbocycle is optionally substituted with one or more substituents selected from halogen.

150. The compound or salt of claim 149, wherein each L is independently selected from .

151. The compound or salt of claim 150, wherein each L is independently selected from.

152. The compound or salt of claim 144, wherein each L is independently selected from a Cl- C4 alkylene optionally substituted with one or more substituents independently selected from halogen and Cl-C4alkyl153. The compound or salt of claim 152, wherein L is selected from , , , and .

154. T m 140, wherein each L is independently selected from an unsubst tuted Cl-C4a y ene.

155. The compound or salt of claim 154, wherein L is selected from and .

156. The compound or salt of claim 155, wherein L is selected from157. The compound or salt of any one of claims 1 to 156, wherein R2is selected from heterocycle, -L-heterocycle, -L-aryl, -L-heteroaryl, and -L-N(R20)2, wherein the heterocycle, the heterocycle portion of -L-heterocycle, are each optionally substituted with one or more R6, and wherein the aryl of the -L-aryl, and the heteroaryl of -L- heteroaryl are each optionally substituted with one or more R7.

158. The compound or salt of claim 157, wherein R2is -L-heterocycle, wherein the heterocycle portion of R2is an optionally substituted heterocycle.

159. The compound or salt of claim 157 or 158, wherein R2is -L-heterocycle, optionally substituted with one or more R6.

160. The compound or salt of any one of claims 1 to 159, wherein Y-R2is selected from , wherein the heterocycle portion is optionally su st tute w t one or more .

161. The compound or salt of any one of claims 139 to 160, wherein the heterocycle portion of R2is a heterocycle optionally substituted with one or more substituents selected from halogen, hydroxy, -CN, Cl-C3hydroxyalkyl, Cl-C3alkyl, Cl-C3haloalkyl, C1-C3alkoxy, and Cl-C3 aminoalkyl.

162. The compound or salt of claim 161, wherein the heterocycle portion of R2is a heterocycle optionally substituted with one or more substituents selected from C1-C3alkyl and halogen.

163. The compound or salt of any one of claims 1 to 162, wherein Y-R2is selected from.

164. The compound or salt of any one of claims 1 to 163, wherein Y-R2is selected from , wherein the heterocycle portion is optionally s 165. The compound or salt of claim 164, wherein R6of R2is independently selected at each occurrence from halogen, hydroxy, Cl-C3hydroxyalkyl, Cl-C3alkyl, Cl-C3haloalkyl, C1- C3alkoxy, cyano, and Cl-C3aminoalkyl.

166. The compound or salt of claim 165, wherein R6of R2is independently selected at each occurrence from C1-C3alkyl and halogen.

167. The compound or salt of claim 166, wherein Y-R2is selected fro ,.

168. T 58, wherein Y-2R is selected from the hy p p y .

169. The compound or salt of claim 168, wherein Y-R2selected fro, and170. The compound or salt of claim 168, wherein Y-R2is selected fro, wherein the heterocycle is optionally substituted.

171. The compound or salt of claim 170, wherein the heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, Cl-C3 alkyl, -N(R5)S(O)2(R5), - OC(O)N(R5)2, =CH2, oxo, =NO-Cl-C3 alkyl, -CH2OC(O)heterocycle, -CH2heterocycle, - CH2OC(O)N(R5)2,and -O-Cl-C3alkyl, wherein the alkyl of -O-Cl-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy.

172. The compound or salt of claims 1 or170 to 171, wherein Y-R2is selected from , ,173. The compound or salt of claim 158, wherein Y-R2is selected fro,, wherein the heterocycle portion is optionally b i d i h R6174. The compound or salt of claims 1 or 173, wherein Y-R2is selected from wherein the heterocycle portion is optionally substituted with one or 175. The compound or salt of claims 1 or 173, wherein Y-R2is selected from , wherein the heterocycle portion is optionally substituted with one o176. The compound or salt of claims 1 or 173, wherein Y-R2is selected fro ,, wherein the heterocycle portion is optionally substituted with177. The compound or salt of any one of claims 173 to 176, wherein the heterocycle is optionally substituted with one or more substituents selected from halogen, hydroxy, Cl- C3 alkyl, -N(R5)S(O)2(R5), -OC(O)N(R5)2, =CH2, oxo, =NO-Cl-C3 alkyl, - CH2OC(O)heterocycle, -CH2heterocycle, -CH2OC(O)N(R5)2,and -O-Cl-C3alkyl, wherein the alkyl of -O-Cl-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy.

178. The compound or salt of any one of claims 173 to 177, wherein each R6is independently selected from halogen.

179. The compound or salt of any one of claims 173 to 178, wherein each R6is independently selected from fluorine.

180. The compound or salt of any one of claims 1 to 160, wherein Y-R2is selected from .

181. The compound or salt of any one of claims 1 to 160, wherein Y-R2is selected from.

182. The compound or salt of claims 1 or 157, wherein R2is -L-N(R20)2.

183. The compound or salt of claim 182, wherein Y-R2is selected from ,.

184. T y substituted with one or more R .

185. The compound or salt of claim 184, wherei .

186. The compound or salt of claim 184, wherein Y-R2.

187. The compound or salt of any one of claims 1 to 15cted from heterocycle, -L-heterocycle, wherein the heterocycle, and the heterocycle portion of -L- heterocycle, are each optionally substituted with one or more R6; and -L-N(R20)2.

188. The compound or salt of claim 187, wherein the heterocycle of R2is selected from e or 189. Te compound or sa t o c a m 88, w ere n t e eterocyc e o s se ected rom ,wherein the heterocycle is optionallysubstituted with one or more.

190. The compound or salt of any one of claims 187 to 189, wherein each R6is independently selected from halogen, hydroxy, Cl-C3 alkyl, Cl-C3 haloalkyl, -N(R5)S(O)2(R5), -CH2OC(O)N(R5)2,and -O-Cl-C3alkyl, wherein the alkyl of -O-Cl-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo, and hydroxy; and wherein each R7is selected from Cl-C3 alkyl, halogen and Cl-C3 haloalkyl.

191. The compound or salt of any one of claims 187 to 189, wherein the heterocycle of R2, the aryl and heteroaryl of R2, and -N(R20)2of R2is selected from is selected fr ,, ,1 om ,,and, wherein the heterocycle, and the heterocycle portion of -L-heterocycle,are each optionally substituted with one or more R6; an.

193. Tis selected from , , ,, , , ,194. The compound or salt of any one of claims 1 to 139, wherein Y-R2is selected from, 195. Td from halogen, hydroxy, Cl-C3 alkyl, Cl-C3 haloalkyl, oxo, C1-C3 alkoxy, Cl-C3 hydroxyalkyl, (C1-C3alkoxy)Cl-C3alkyl-, =CH2, =CF2, -OC(O)N(R5)2, =NO-Cl-C3alkyl, - N(R5)S(O)2(R5), -CH2OC(O)N(R5)2, -CH2OC(O)heterocycle, -(CH2)0-1S-heterocycle, - (CH2)0-1-O-heterocycle, and -O-Cl-C3 alkyl; wherein the alkyl of -O-Cl-C3alkyl is optionally substituted with substituents selected from heterocycle, oxo and hydroxy; and wherein the heterocycle of -(CH2)0-1-O-heterocycle and -(CH2)0-1-S-heterocycle are each optionally substituted with one or more substituents selected from C1-6alkyl, C1-6haloalkyl, C1-6alkyl-OR20, and -OR20.

196. The compound or salt of claim 195, wherein each R6is independently selected from, , , ,nd 197. T elected from, , ,, ,, , ,, ,, , ,,, ,198. The compound or salt of any one of claims 1 to 157, wherein Y is -O- and R2is selected from L-6-membered heterocycle wherein L is selected from an optionally substituted C1- C4alkylene, and wherein the heterocycle is optionally substituted with one or more R6, wherein each R6is preferably selected from halogen, Cl-C4 alkyl, and Cl-C4 haloalkyl.

199. The compound or salt of any one of claims 1 to 157, wherein Y is -O- and R2is selected from L-8-membered heterocycle wherein L is selected from an optionally substituted C1- C4alkylene, and wherein the heterocycle is optionally substituted with one or more R6, wherein each R6is preferably selected from halogen, Cl-C4 alkyl, and Cl-C4 haloalkyl.

200. A pharmaceutical composition comprising a compound or salt of any one of claims 1 to 199 and a pharmaceutically acceptable excipient.

201. A method of treating a disease or disorder, comprising administering to a patient in need thereof the pharmaceutical composition of claim 200 or the compound or salt of any one of claims 1 to 199.

202. The method of claim 201, wherein the disease or disorder is a cancer selected from: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma; Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Kaposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor (nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma); Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Biliary tract: gall bladder carcinoma, ampullary carcinoma, cholangiocarcinoma; Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors; Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma sarcoma);Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma (serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma); Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma); Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Kaposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis; and Adrenal glands: neuroblastoma.

203. The method of claim 202, wherein the disease or disorder is a cancer, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer; or wherein the cancer is a tumor cancer.

204. The method of any one of claims 202 to 203, wherein the cancer is non-small cell lung cancer, small cell lung cancer, colorectal cancer, rectal cancer or pancreatic cancer.

205. The method of any one of claims 202 to 203, wherein the cancer is non-small cell lung cancer.

206. The method of any one of claims 202 to 203, wherein the cancer is small cell lung cancer.

207. The method of any one of claims 202 to 203, wherein the cancer is colorectal cancer.

208. The method of any one of claims 202 to 203, wherein the cancer is rectal cancer.

209. The method of any one of claims 202 to 203, wherein the cancer is pancreatic cancer.

210. The method of any one of claims 202 to 203, wherein the cancer is a solid tumor cancer.

211. The method of any one of claims 201 to 210, wherein the disease or disorder is a KRas G12D mutant-associated cancer.

212. The method of any one of claims 201 to 210, wherein the disease or disorder is a KRas G12V mutant-associated cancer.

213. The method of any one of claims 201 to 210, wherein the disease or disorder is a KRas G12D or other G12 mutants-associated cancer.

214. A method of inhibiting KRas G12D and / or other G12 mutants, using a compound or salt of any one of claims 1 to 199 or a pharmaceutical composition of claim 200.

215. A method of inhibiting KRas G12D and / or other G12 mutants, using a compound or salt of any one of claims 1 to 199 or a pharmaceutical composition of claim 200216. A method of inhibiting KRas G12D and / or other G12 alleles, using a compound or salt of any one of claims 1 to 199 or a pharmaceutical composition of claim 200.

217. A method of inhibiting KRas G12D and / or other alleles, using a compound or salt of any one of claims 1 to 199 or a pharmaceutical composition of claim 200.

218. Use of a compound of any one of claims 1-199 thereof in the preparation of a target protein degrading compound by using chemical modification of compound of any one of claims 1-199.

219. A bifunctional compound composed of a target protein-binding moiety and an E3 ubiquitin ligase-binding moiety, wherein the target protein-binding moiety is derived from the compound of any of claims 1-199.

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